In 1926, he joined the Liberal rebellion in support of the presidential claims of Juan Bautista Sacasa, his wife's uncle. Although Somoza failed to distinguish himself in battle, leading an unsuccessful attack on the garrison at San Marcos, his unaccented English allowed him to act as an interpreter during the U.S.-brokered negotiations between the warring parties.

In the government of President José María Moncada, to whom he was distantly related, he served as governor of the department of León, Nicaraguan Consul to Costa Rica and Foreign Minister. Despite his limited military experience, Somoza was able to rise through the ranks of the Nicaraguan National Guard (Guardia Nacional), the constabulary force organized by the United States Marines.

After waging a bitter, six-year struggle with the forces of General Augusto Sandino, in January 1933, the Marines evacuated the country, following the election of Juan Bautista Sacasa as President. At the urging of the U.S. Ambassador Matthew E. Hanna, Somoza García was appointed as director of the National Guard. During peace talks, Somoza ordered the assassination of General Sandino on February 21, 1934 in violation of a safe conduct agreement. Sandino's assassination was followed by the murder of former Sandino supporters by the National Guard. In June 1936, Somoza forced Sacasa to resign.

During World War II, the government confiscated the properties of Nicaragua's small, but economically influential, German community and sold them to Somoza and his family at ridiculously low prices. By 1944, Somoza was the largest landowner in Nicaragua, owning fifty-one cattle ranches and forty-six coffee plantations, as well as several sugar mills and rum distilleries. Somoza named himself director of the Pacific Railroad, linking Managua to the nation's principal port, Corinto, which moved his merchandise and crops for free and maintained his vehicles and agricultural equipment. He also made substantial profits by granting concessions to foreign (primarily U.S.) companies to exploit gold, rubber and timber, for which he received 'executive levies' and 'presidential commissions.' He passed laws restricting imports and organized contraband operations, which sold merchandise through his own stores. He also extracted bribes from illegal gambling, prostitution and alcohol distilling. By the end of the decade, he had acquired a fortune estimated to be US$40 million.

Though Nicaragua was on the Lend Lease in World War II, the unwillingness of Nicaragua to actually fight meant it was given obsolete equipment (most of it being either purchased from Russia, Spain and Portugal or captured German equipment) and no Western training.

A series of puppets ruled for the remainder of the year, and, in December, Somoza was elected president by the margin of 107,201 votes to 100, taking office on New Year's Day 1937. Somoza, popularly known as "Tacho," amended the Constitution to centralize all power in his hands. Family members and key supporters monopolized key positions in the government and military. While opposition parties continued to exist on paper, in practice, the system was heavily rigged in favor of Somoza's Nationalist Liberal Party. Throughout the 1930s and 1940s, he acquired immense personal wealth, primarily through investments in agricultural exports, particularly coffee, cotton and cattle. Following the massacre of Sandino's followers, he acquired most of the land which had been granted to them by Sacasa.

In 1944, under pressure from the U.S., Somoza agreed not to run for re-election, and had the Nationalist Liberal Party nominate an elderly doctor named Leonardo Argüello, with Somoza using the National Guard to secure his election. Upon being sworn in as President in May 1947, Argüello displayed considerable independence, attempting to reduce the power of the National Guard and the control of Somoza and his associates over the economy. Less than a month later, Somoza orchestrated another coup, naming one of his wife's uncles, Benjamín Lacayo, as President.

When the administration of U.S. President, Harry Truman, refused to recognize the new government, a Constituent Assembly was convened, which appointed Somoza's uncle, Víctor Manuel Román y Reyes, as President. In another heavily rigged election, Somoza García again became President in 1950. In the 1950s, he reorganized and streamlined his business empire, founding a merchant marine company, several textile mills, a national airline (LANICA, short for Líneas Aéreas de Nicaragua) and a new container port on the Pacific near Managua, which he named Puerto Somoza (after the Sandinistas came to power they renamed it Puerto Sandino). He also acquired properties in the United States and Canada.

In 1955, the constitution was amended to allow him to run for another term. Shortly after being nominated, he was shot on 21 September 1956 by the poet Rigoberto López Pérez in the city of León, and died several days later after being sent to a Panama Canal Zone hospital. His older son, Luis Somoza, succeeded him.

Though the Somozas were generally regarded as ruthless dictators, the United States continued to support them as a non-communist stronghold in Nicaragua. President Franklin D. Roosevelt (FDR) supposedly remarked in 1939 that "Somoza may be a son of a bitch, but he's our son of a bitch." According to historian David Schmitz, however, researchers and archivists who have searched the archives of the Franklin D. Roosevelt Presidential Library have found no evidence that Roosevelt ever made this statement. The statement first appeared in the November 15, 1948 issue of Time magazine and was later mentioned in a March 17, 1960 broadcast of CBS Reports called "Trujillo: Portrait of a Dictator". In this broadcast, however, it was asserted that FDR made the statement in reference to Rafael Trujillo of the Dominican Republic. It should be further noted that this statement has been attributed to a variety of United States presidential administrations in regard to foreign dictators. Thus the statement remains apocryphal at this point, though Roosevelt and future presidents certainly supported the Somoza family and their rule over Nicaragua.

Somoza's sons, Luis Somoza and Anastasio Somoza Debayle, ruled the country directly or through figurehead politicians for the next 23 years. Despite widespread corruption and repression of dissent, they were able to hold onto power because the United States viewed them as anti-communist stalwarts and a source of stability. His daughter Lillian Somoza Debayle, born in León, Nicaragua, on 3 May 1921, married Guillermo Sevilla Sacasa, Nicaraguan Ambassador to the United States during his brothers in law's rule. He also had a son by an unknown mother named José R. Somoza.

He is entombed at Woodlawn Park Cemetery (now Caballero Rivero Woodlawn North Park Cemetery and Mausoleum) in Miami, Miami - Dade County, Florida.