On August 13, 1913, at the age of 22, Trujillo married Aminta Ledesma, a reputable young girl from his hometown of San Cristóbal. They had two daughters: Genoveva, who was born and died in 1914, and Flor de Oro Trujillo Ledesma, born in 1915 and who later married Porfirio Rubirosa. The marriage, not mentioned in later official biographies, ended in a divorce in 1925. On March 30, 1927, Trujillo married Bienvenida Ricardo, a girl from Montecristi and the daughter of Buenaventura Ricardo Heureaux. A year later he met Maria de los Angeles Martínez Alba "la españolita", and had an affair with her. She gave birth to Rafael Leonidas Ramfis on June 5, 1929. He divorced Bienvenida in 1935 and married Martínez. A year later he had a daughter with Bienvenida, named Odette Trujillo Ricardo. Trujillo's two children with Maria Martínez were María de los Angeles, (Angelita), born in Paris on June 10, 1939, and Leonidas Rhadamés, born on December 1, 1942. Ramfis and Rhadamés were named after characters in Giuseppe Verdi's opera Aida. In 1937, Trujillo met Lina Lovatón Pittaluga, an upper-class debutante with whom he had two children, Yolanda in 1939, and Rafael, born on June 20, 1943.

Two of Trujillo's brothers, Héctor and José Arismendy, held positions in his government. José Arismendy Trujillo oversaw the creation of "La Voz Dominicana", the main radio station and later, the television station which became the fourth in the continent.

Trujillo's childhood passed relatively without incidents. His basic education was irregular and quite limited. At six he was registered in the school of Juan Hilario Meriño. One year later he transferred to the school of Broughton, where he was a pupil of Eugenio María de Hostos, and remained there for three or four years. At sixteen Trujillo got a job as a Morse code telegraph operator. He became a member of "The 44", a small gang.

In 1916 Trujillo worked for two years in the sugar industry eventually as a guarda campestre.

In 1916, the U.S. occupied the island due to threats of defaulting on foreign debts. The occupying force soon established a Dominican army constabulary to restore order. Seeing opportunity, Trujillo impressed the recruiters and was soon promoted through the ranks. When U.S. troops left the island in 1924, they left Trujillo in charge.

The rebellion against President Horacio Vásquez broke out in 1930 in Santiago, and the rebels marched toward Santo Domingo. Trujillo was ordered to subdue the rebellion, but when the mutineers arrived at the capital on February 26, they encountered no resistance. Rebel leader Rafael Estrella was proclaimed as acting-president when Vásquez resigned. Trujillo then became the nominee of the newly-formed Dominican Party in the 1930 presidential election. He won on May 16, officially registering 95 percent of the vote — an implausibly high total that could have been obtained only by means of massive fraud. A judge actually declared the election fraudulent, but was forced to flee. On August 16, the then 38-year-old general took office, wearing a sash with the motto, "Dios y Trujillo" (God & Trujillo). He immediately assumed dictatorial powers.

Three weeks later, the destructive Hurricane San Zenon hit Santo Domingo and left more than 3,000 dead. With relief money from the American Red Cross, Trujillo rebuilt the city. On August 16, 1931, the first anniversary of his inauguration, Trujillo made the Dominican Party the sole legal political party. However, the country had effectively been a one-party state since Trujillo had been sworn in. Government employees were required to "donate" 10 percent of their salary to the national treasury, and there was strong pressure on adult citizens to join the party. Party members were required to carry a membership card, the "palmita," and a person could be arrested for vagrancy without the card. Those who did not contribute, or join the party, did so at their own risk. Opponents of the regime were mysteriously killed. In 1934, Trujillo, who had promoted himself to generalissimo of the army, was up for re-election. Although he would have won in any case as there was virtually no organized opposition left in the country, Trujillo dispensed even with these formalities. Instead, he relied upon "civic reviews," with large crowds shouting their loyalty to the government.

At the suggestion of Mario Fermín Cabral, Congress voted overwhelmingly in 1936 to rename the capital from Santo Domingo to Ciudad Trujillo. The province of San Cristobal was created as "Trujillo," and the nation's highest peak, Pico Duarte, was renamed in his honor. Statues of "El Jefe" were mass-produced and erected across the Republic, and bridges and public buildings were named in his honor. The nation's newspapers now had praise for Trujillo as part of the front page, and license plates included the slogan "Viva Trujillo!" An electric sign was erected in Ciudad Trujillo so that "Dios y Trujillo" could be seen at night as well as in the day. Eventually, even churches were required to post the slogan, "Dios en cielo, Trujillo en tierra" (God in Heaven, Trujillo on Earth). As time went on, the order of the phrases was reversed (Trujillo on Earth, God in Heaven). Trujillo was recommended for the Nobel Peace Prize by his admirers, but the committee declined the suggestion. When he received (or summoned) a visitor, his four bodyguards would have submachine guns trained upon the "guest" during the meeting.

Trujillo was eligible to run again in 1938, but, citing the U.S. example of two presidential terms, he stated that "I voluntarily, and against the wishes of my people, refuse re-election to the high office." The Dominican Party nominated Trujillo's handpicked successor, 71 year old vice-president Jacinto Bienvenido Peynado. As the government had banned all other political parties, the election of Peynado and Manuel de Jesús Troncoso was merely a formality. Meanwhile, Trujillo limited himself to being the "Generalissimo" while only nominally ceding control to President Peynado. Peynado increased the size of the electric "Dios y Trujillo" sign and died on March 7, 1940, with Troncoso serving out the rest of the term. In 1942, with President Franklin D. Roosevelt having run for a third term in the United States, Trujillo ran for president again and won overwhelmingly. He served two terms, having lengthened a presidential term to five years. In 1952, his brother, Héctor Trujillo, nominally assumed the presidency.

His daughter Angelita was designated "queen" of the 1955 Fair of Peace and Fraternity of the Free World, a pompous event that cost US$30 million. Fair organizers declared Trujillo's semi-literate wife María Martínez a 'writer and philosopher'.

Brutal oppression of actual or perceived members of any opposition was a key feature of Trujillo's rule right from the beginning in 1930 when his gang, "The 44", under its leader Miguel Angel Paulino drove through the street in their red Packard carro de la muerte (death car). Imprisonments and killings were later handled by the SIM, the secret police, efficiently organized by Johnny Abbes. Some cases reached international attention such as the Galindez case and the murder of the Mirabal sisters.

Trujillo was known for his open-door policy, accepting Jewish refugees from Europe, Japanese migration during the 1930s, and exiles from Spain following its civil war. He developed a uniquely Dominican policy of racial discrimination, Antihaitianismo ("anti-Haitianism"), targeting the mostly-black inhabitants of his neighboring country and those within the Platano Curtain, including many darker Dominican citizens. At the 1938 Evian Conference the Dominican Republic was the only country willing to accept many Jews and offered to accept up to 100,000 refugees on generous terms. In 1940 an agreement was signed and Trujillo donated 26,000 acres of his properties for settlements. The first settlers arrived in May 1940; eventually some 800 settlers came to Sosua and most moved later on to the United States. Refugees from Europe broadened the Dominican Republic's tax base and added more whites to the predominately mixed-race nation. The government favored Caucasian refugees over others while Dominican troops expelled illegal aliens, resulting in the 1937 Parsley Massacre of Haitian immigrants.

The Trujillo regime greatly expanded the Vedado del Yaque, a nature reserve around the Yaque del Sur River. In 1934 he created the nation's first national park, banned the slash and burn method of clearing land for agriculture, set up a forest warden agency to protect the park system, and banned the logging of pine trees without his permission. While he acted in the name of environmentalism, he probably wanted to create logging monopolies for his private companies. In the 1950s the Trujillo regime commissioned a study on the hydroelectric potential of damming the Dominican Republic's waterways. The commission concluded that only forested waterways could support hydroelectric dams, so Trujillo banned logging in potential river watersheds. After his assassination in 1961, logging resumed in the Dominican Republic. Squatters burned down the forests for agriculture, and logging companies clear-cut parks and potential hydroelectric watersheds, thus reducing the Dominican Republic's potential generation of hydroelectric energy. In 1967, then-President Joaquín Balaguer launched military strikes against illegal logging.

Trujillo's anti-communism tended toward a peaceful coexistence with the United States government. During World War II Trujillo sided with the Allies and declared war on Germany and Japan on December 11, 1941. While there was no military participation the Dominican Republic thus became a founding member of the United Nations. Trujillo encouraged diplomatic and economic ties with the U.S., but his policies often caused friction with other nations of Latin America, especially Costa Rica and Venezuela. He maintained friendly relations with Franco of Spain, Peron of Argentina, and Somoza of Nicaragua. Towards the end of his rule, his relationship with the United States deteriorated.

Trujillo paid special attention to improving the armed forces. Military personnel received generous pay and perks under his rule, and their ranks as well as equipment inventories expanded. Trujillo maintained control over the officer corps through fear, patronage, and the frequent rotation of assignments, which inhibited the development of strong personal followings. The establishment of state monopolies over all major enterprises in the country brought riches to the Trujillos through price manipulation and embezzlement.
Early on, Trujillo determined that the financial affairs of the Dominican Republic needed to be put in order, and that included the termination of the role of the United States as the administrator of Dominican customs and finances — a situation that had existed since 1924. Negotiations started in 1936 and lasted four years. On September 24, 1940, Trujillo and Cordell Hull signed the Hull-Trujillo Treaty whereby the United States relinquished its control of customs and the Dominican Republic made arrangements to repay its debts.

Haiti, the smaller but more densely populated country of the island, had invaded and occupied the Dominican Republic from 1822-44. Encroachment by Haiti was an ongoing process, and when Trujillo took over, specifically the northeast border region became more and more "Haitinized". The actual border itself was poorly defined. In 1933 Trujillo met the Haitian President Stenio Vincent to settle the border issue. By 1936 a settlement was reached and signed. At the same time, Trujillo tried to plot against the Haitian government by linking up with General Calixte, Commander of the Garde d'Haiti, and Elie Lescot, at that time the Haitian ambassador in Ciudad Trujillo (Santo Domingo). After the settlement, when further border incursions occurred, the Parsley Massacre was initiated by Trujillo. In 1937, claiming that Haiti was harboring his former Dominican opponents, Trujillo ordered an attack on the border, slaughtering tens of thousands of Haitians as they tried to escape. The number of the dead is still unknown, though it is now calculated between 20,000 and 30,000. Trujillo hoped for a war with Haiti and control over the entire island of Hispaniola. The Haitian response was muted, but eventually called for an international investigation. Under pressure from Washington, Trujillo agreed to a reparation settlement in January 1938 that involved the payment of US$750,000. By the next year the amount had been reduced to US$525,000 (US$ 7,955,581.4 in 2010); 30 dollars per victim, of which only 2 cents were given to survivors, due to corruption in the Haitian bureaucracy.

In 1941, Lescot, who had received financial support from Trujillo, succeeded Vincent as President of Haiti. Trujillo expected Lescot to be a puppet, but Lescot turned against him. Trujillo unsuccessfully tried to assassinate him in a 1944 plot, and then published their correspondence and discredited him. Lescot was exiled after a 1946 palace coup. In 1947 Dominican exiles, including Juan Bosch, had concentrated in Cuba. With the approval and support of the Grau government, an expedition force was trained with the intent to invade the Dominican Republic and overthrow Trujillo. However, international pressure, including from the United States, led to the abortion of the expedition. In turn, when Fulgencio Batista was in power, Trujillo initially supported anti-Batista supporters of Prio in Oriente in 1955, however weapons Trujillo sent were soon inherited by Castro's insurgents when Prio allied with Castro. After 1956, when Trujillo saw that Castro was gaining ground, he started to support Batista with money, planes, equipment, and men. Trujillo, convinced that Batista would prevail, was very surprised when he showed up as a fugitive after being ousted. Trujillo kept Batista until August 1959 as a "virtual prisoner". Only after paying between three to four million dollars could Batista leave for Portugal, which had granted him a visa.

Castro made threats to overthrow Trujillo, and Trujillo responded by increasing the budget for national defense. A foreign legion was formed to defend Haiti, as it was expected that Castro might invade the Haitian part of the island first and remove Duvalier as well. A Cuban plane with 56 fighting men landed near Constanza on Sunday, June 14, 1959, and six days later more invaders brought by two yachts landed at the north coast. However, the Dominican Army prevailed. In turn, in August 1959, Johnny Abbes attempted to support an anti-Castro group led by Escambray near Trinidad, Cuba. The attempt, however, was thwarted when Cuban troops surprised a plane he had sent when it was unloading its cargo.

By the late 1950s, opposition to Trujillo's regime was starting to build to a fever pitch. A younger generation of Dominicans had been born who had no memory of the instability and poverty that had preceded him. Many clamored for democratization. The Trujillo regime responded with greater repression. The Military Intelligence Service (SIM) secret police, led by Johnny Abbes, remained as ubiquitous as before. Other nations ostracized the Dominican Republic, compounding the dictator's paranoia.

Trujillo began to interfere more and more into the domestic affairs of other neighboring countries. Trujillo expressed great contempt for Venezuela's president Rómulo Betancourt. An established and outspoken opponent of Trujillo, Betancourt associated with Dominicans who had plotted against the dictator. Trujillo developed an obsessive personal hatred of Betancourt and supported numerous plots of Venezuelan exiles to overthrow him. This pattern of intervention led the Venezuelan government to take its case against Trujillo to the Organization of American States (OAS). This development infuriated Trujillo, who ordered his foreign agents to plant a bomb inside Betancourt's car. The assassination attempt, carried out on Friday, June 24, 1960, injured but did not kill the Venezuelan president. The Betancourt incident inflamed world opinion against Trujillo. Outraged OAS members voted unanimously to sever diplomatic relations with Trujillo's government and impose economic sanctions on the Dominican Republic. The brutal murder on November 25, 1960 of the three Mirabal sisters, Patria, María and Minerva, who opposed Trujillo's dictatorship, further increased discontent against his repressive rule. The relationship with the dictator had become an embarrassment to the United States and became fractured after the Betancourt incident.

On the night of Tuesday, May 30, 1961, Trujillo was shot dead on San Cristobal Avenue, Santo Domingo. He was the victim of an ambush plotted by Modesto Diaz, Salvador Estrella Sadhalá, Antonio de la Maza, Amado García Guerrero, Manuel Cáceres Michel (Tunti), Juan Tomás Diaz, Roberto Pastoriza, Luis Amiama Tió, Antonio Imbert Barrera, Pedro Livio Cedeño, and Huáscar Tejeda. According to U.S. reporter Bernard Diederich, the Central Intelligence Agency (CIA) planned the operation to kill the dictator. In a report to the Deputy Attorney General of the United States, CIA officials described the agency as having "no active part" in the assassination and only a "faint connection" with the groups that planned the killing. However, an internal CIA memorandum states that an Office of Inspector General investigation into Trujillo's murder disclosed "quite extensive Agency involvement with the plotters." G. Pope Atkins writes that "the CIA arranged, planned and executed the assassination" using their elite paramilitary operations officers from the Special Activities Division.

Trujillo's family tried to flee with his body upon his boat Angelita, but were turned back. His funeral was that of a statesman with the long procession ending in his hometown of San Cristóbal, where his body was first buried. Then-president Joaquín Balaguer gave the eulogy. After this, the people voted for the Trujillo family to leave the country, so his son, Ramfis Trujillo, came back to relocate his father's body outside of the country. Trujillo was buried in Paris, in Père Lachaise Cemetery, at the request of his relatives.

Trujillo's "central arch" was his instinct for power. This was coupled with an intense desire for money and the realization that money was a source and support of power. Up at four in the morning, he exercised, studied the newspaper, read reports, and completed papers prior to breakfast; at the office by nine, he continued his work, and took lunch by noon. After a walk, he continued to work until 7:30 PM. After dinner, he attended functions, held discussions, or was driven around incognito in the city "observing and remembering." He was methodical, punctual, secretive, and guarded, having no true friends, only associates and acquaintances. For his associates his actions towards them were unpredictable. Trujillo and his family amassed enormous wealth. He acquired property including cattle lands on a grand scale, and went into meat and milk production, operations that soon evolved into monopolies. Other industries were salt, sugar, tobacco, lumber, and lottery where he or family members held controlling interests or monopolies. Already in 1937 Trujillo's annual income was about $1.5 million; at the time of his death the state took over 111 Trujillo companies. His love of fine and ostentatious clothing was displayed in elaborate uniforms and fine suits of which he collected almost two thousand. Known to be fond of neckties, he amassed a collection of over ten thousand of them. Trujillo doused himself with perfume and liked gossip. His sexual appetite was enormous, and he preferred mulatto women with full bodies, later tending more to "very young" women. Women were supplied and procured by many who sought his favors, and later he had an official on his Palace staff to organize the sessions. Typically encounters lasted once or twice, but favorites were kept for longer terms. If women were unwilling to submit, Trujillo would know how to apply pressure on the family to get his way. Trujillo was such a baseball lover that he invited many black players from the US where they could not play because the teams were segregated. Leroy Robert "Satchel" Paige, a Negro League player, went to the Caribbean and Latin America, where the teams were all integrated. He pitched for a team organized by Trujillo. He was trying to gain popularity so he created the "Ciudad Trujillo Team." He paid Paige $30,000 for winning the Dominican championship. Paige fled the Dominican Republic with his teammates directly after being paid for fear of reprisals by Trujillo's enemies. Trujillo was energetic and fit. Medically, he was quite healthy in general, but suffered from chronic lower urinary infections and, later, prostate problems. In 1934, Dr. Georges Marion was called from Paris to perform 3 urologic procedures on Trujillo. Over time Trujillo acquired numerous accommodations. His favorite place was Las Caobas on Estancia Fundacion near San Cristobal. He used Estancia Ramfis (after 1953 it became the Foreign Office), Estancia Rhadames and a home at Playa de Najayo. Other places he owned he frequented rarely such as places in Santiago, Constanza, La Cumbre, San Juan de las Matas, and more. Further, he maintained a penthouse at the Embajador Hotel in the capital. While Trujillo was a nominally a Catholic, his devotion was limited to a perfunctory role in public affairs; he placed faith in local superstitions.

There is much controversy in the Dominican Republic at this time (2009) on the 48th year anniversary of his death. There is talk of trying to return the remains of Trujillo to DR and place his body along with the national heroes. Most of the people are strongly opposed to this idea.