Santa Anna was born in Xalapa, Veracruz, New Spain, on February 21, 1794; he was the son of a respected Spanish colonial family, Antonio López de Santa Anna and Manuela Pérez de Lebrón, who belonged to the criollo middle class. They were wealthy enough to send their son to school. His father served for a time as a sub-delegate for the Spanish province of Veracruz, New Spain for the Royal Army. In June 1810, Santa Anna at age 16 became a cadet and was sent to the Fijo de Vera Cruz infantry regiment under the command of Joaquín de Arredondo. In 1810, the same year that Miguel Hidalgo y Costilla started Mexico’s first attempt to gain independence from Spain, Santa Anna joined the colonial Spanish Army under Joaquín de Arredondo, who taught him much about dealing with Mexican nationalist rebels. In 1811, Santa Anna was wounded in the left arm by a native Chichimec arrow. It was during the campaign under Colonel Joaquin Arredondo in the town of Amoladeras, in the state of San Luis Potosí. In 1813, Santa Anna served in Texas against the Gutiérrez/Magee Expedition, and at the Battle of Medina, in which he was cited for bravery. He was promoted quickly. He became a second lieutenant in February 1812, and first lieutenant before the end of that year. In the aftermath of the rebellion, the young officer witnessed Arredondo's fierce counter-insurgency policy of mass executions. Historians have speculated that Santa Anna modeled his policy and conduct in the Texas Revolution on his experience under Arredondo.

During the next few years, in which the war for independence reached a stalemate, Santa Anna erected villages for displaced citizens near Veracruz. He also pursued gambling, a vice that would follow him all through his life. In 1816 Santa Anna was promoted to captain. He conducted occasional campaigns to suppress Native Americans or to restore order after a tumult had begun. Mexican territory extended to present-day Oregon in the north and Panama in the south. It was a territory too vast for the Spanish Crown to control. In 1821, Santa Anna declared his loyalty for El Libertador (The Liberator): the future Emperor of Mexico, Agustín de Iturbide. He rose to prominence by quickly driving Spanish forces out of the vital port city of Veracruz that same year. Iturbide rewarded him with the rank of general. Santa Anna exploited his situation for personal gain. He acquired a large hacienda and at the same time continued gambling. Santa Anna was ambiguous in support of Iturbide, who was never popular and needed the military to maintain his power. Santa Anna’s normal loyalty was to ally with the wealthy and privileged, but his immediate concern was to be on the winning side in any battle. Switching allegiances never troubled him. Santa Anna declared himself retired, "unless my country needs me".

In 1822 Santa Anna went over to the camp of military leaders supporting the plan to overthrow Iturbide. In December 1822 Santa Anna and General Guadalupe Victoria signed the Plan de Casa Mata to abolish the monarchy and transform Mexico into a republic. In May 1823, following Iturbide's resignation, Victoria became the first president of Mexico. Santa Anna's role in the overthrow of Iturbide gained support from other leaders, although they knew of his propensity for switching sides in an opportunistic manner. By 1824, Vicente Guerrero appointed Santa Anna governor of the state of Yucatán. On his own initiative, Santa Anna prepared to invade Cuba, which remained under Spanish rule, but he possessed neither the funds nor sufficient support for such a venture. In 1828, Santa Anna, Vicente Guerrero, Lorenzo Zavala and other politicians staged a coup against the elected President Manuel Gómez Pedraza. On 3 December 1828, the army shelled the National Palace; the election results were annulled and Guerrero took over as president.

In 1829, Spain made a final attempt to retake Mexico in Tampico with an invading force of 2,600 soldiers. Santa Anna marched against the Barradas Expedition with a much smaller force and defeated the Spaniards, many of whom were suffering from yellow fever. The defeat of the Spanish army not only increased Santa Anna’s popularity but also consolidated the independence of the new Mexican republic. Santa Anna was declared a hero. From then on, he styled himself "The Victor of Tampico" and "The Savior of the Motherland". His main act of self-promotion was to call himself "The Napoleon of the West". In a December 1829 coup, Vice-President Anastasio Bustamante rebelled against President Guerrero, had him executed, and on January 1, 1830 took over the presidency. In 1832 a rebellion started against Bustamante, intended to install Manuel Pedraza, whose election in 1828 recognized the rebels as legitimate. The rebels offered the command to Gen. Santa Anna. In August 1832, Bustamante temporarily appointed Melchor Múzquiz to the post of president. He moved against the rebels and defeated them at Gallinero. Dolores Hidalgo, Guanajuato and Puebla marched to meet the forces of Santa Anna, who were approaching the town of Puebla. After two more battles Bustamante, Pedraza and Santa Anna signed the agreement Zavaleta (21-23 December 1832) to install Pedraza as president. Bustamente went into exile. Santa Anna accompanied the new president on Jan. 3, 1833, and joined him in the capital. President Pedraza convened Congress. It elected Santa Anna as President on April 1 1833. President Santa Anna appointed as Vice-President, Valentín Gómez Farías, and largely left the governing of the nation to him. Farias began to implement liberal reforms, mostly aimed against the army and the Roman Catholic Church, a state religion in Mexico. Such reforms as abolishing tithing as a legal obligation, and the seizure of church property and finances, prompted Mexican Conservatives to turn to Santa Anna to take power again. At their behest, Santa Anna denounced the administration of Vice-President Farias, and forced him and his main supporters to flee to the United States. He formed a new Catholic, centralist, conservative government which replaced the 1824 constitution with the new constitutional document, entitled "The Seven Laws" (Constitution of 1836). Santa Anna dissolved the Congress and began the centralization of power. The regime became a centralized dictatorship backed by the military.

Several states openly rebelled against the changes: Coahuila y Tejas (which was to become the Republic of Texas), San Luis Potosí, Querétaro, Durango, Guanajuato, Michoacán, Yucatán, Jalisco, Nuevo León, Tamaulipas and Zacatecas. Several of these states formed their own governments, the Republic of the Rio Grande, the Republic of Yucatan, and the Republic of Texas. (Only the Texans defeated Santa Anna and retained their independence). Their fierce resistance was possibly fueled by reprisals Santa Anna committed against his defeated enemies. The Zacatecan militia, the largest and best supplied of the Mexican states, led by Francisco Garcia, was well armed with .753 caliber British 'Brown Bess' muskets and Baker .61 rifles. Nonetheless, after two hours of combat on May 12, 1835, Santa Anna's "Army of Operations" defeated the Zacatecan militia and took almost 3,000 prisoners. Santa Anna allowed his army to loot Zacatecas for forty-eight hours. After defeating Zacatecas, he planned to move on to Coahuila y Tejas to quell the rebellion there, which was being supported by settlers from the United States (aka Texians). Like other states discontented with the central Mexican authorities, the Texas department of the Mexican state of Coahuila y Tejas rebelled in late 1835 and declared itself independent on March 2, 1836. Santa Anna marched north to bring Texas back under Mexican control. On March 6, 1836, at the Battle of the Alamo, Santa Anna's forces killed 187-250 Texan defenders and later executed more than 350 Texan prisoners at the Goliad Massacre (March 27, 1836). Following the defeat, the Texans were reorganized under Sam Houston. Houston and his soldiers defeated Santa Anna at the Battle of San Jacinto on April 21, 1836, with the Texan army shouting "Remember Goliad, Remember the Alamo!" The day after the battle on April 22, a small band of Texan forces captured Santa Anna, dressed in a dragoon private's uniform and hiding in a marsh. Acting Texas president David G. Burnet and Santa Anna signed the Treaties of Velasco: "in his official character as chief of the Mexican nation, he acknowledged the full, entire, and perfect Independence of the Republic of Texas." In exchange, Burnet and the Texas government guaranteed Santa Anna's life and transport to Veracruz. Back in Mexico City, however, a new government declared that Santa Anna was no longer president and that the treaty with Texas was null and void.

After some time in exile in the United States, and after meeting with U.S. president Andrew Jackson in 1837, Santa Anna was allowed to return to Mexico aboard the USS Pioneer (1836) to retire to his hacienda in Veracruz, called Manga de Clavo. In 1838, Santa Anna had a chance for redemption from the loss of Texas. After Mexico rejected French demands for financial compensation for losses suffered by French citizens, France sent forces that landed in Veracruz, Mexico in the Pastry War. The Mexican government gave Santa Anna control of the army and ordered him to defend the nation by any means necessary. He engaged the French at Veracruz. During Mexican retreat after a failed assault, Santa Anna was hit in the leg and hand by cannon fire. His shattered ankle required amputation of much of his leg, which he ordered buried with full military honors. Despite Mexico's final capitulation to French demands, Santa Anna used his war service to re-enter Mexican politics as a hero. He never allowed Mexico to forget him and his sacrifice in defending the fatherland. Santa Anna famously used a prosthetic cork leg; during the Mexican-American War, it was captured and kept by American troops. The false leg is displayed at the Illinois National Guard Museum in Springfield. The Mexican government has repeatedly asked for its return.

Soon after, as Bustamante's presidency turned chaotic, supporters asked Santa Anna to take control of the provisional government. Santa Anna became president for the fifth time, taking over a nation with an empty treasury. The war with France had weakened Mexico, and the people were discontented. Also, a rebel army led by Generals Jose Urrea and José Antonio Mexía was marching towards the capital in opposition to Santa Anna. Commanding the army, Santa Anna crushed the rebellion in Puebla. Santa Anna's rule was more dictatorial than his first administration. Anti-Santanista newspapers were banned and dissidents jailed. In 1842, he directed a military expedition into Texas, which resulted in no gain but persuaded more Texans of the potential benefits of annexation by the more powerful United States. Trying to restore the treasury, Santa Anna raised taxes, but this aroused resistance. Several Mexican states stopped dealing with the central government, and Yucatán and Laredo declared themselves independent republics. With resentment growing, Santa Anna stepped down from power. Fearing for his life, he tried to elude capture, but in January 1845 he was apprehended by a group of Indians near Xico, Veracruz. They turned him over to authorities, and Santa Anna was imprisoned. His life was spared, but the dictator was exiled to Cuba.

In 1846, the United States declared war on Mexico. Santa Anna wrote to Mexico City saying he had no aspirations to the presidency, but would eagerly use his military experience to fight off the foreign invasion of Mexico as he had in the past. President Valentín Gómez Farías was desperate enough to accept the offer and allowed Santa Anna to return. Meanwhile, Santa Anna had secretly been dealing with representatives of the United States, pledging that if he were allowed back in Mexico through the U.S. naval blockades, he would work to sell all contested territory to the United States at a reasonable price. Once back in Mexico at the head of an army, Santa Anna reneged on both of these agreements. Santa Anna declared himself president again and unsuccessfully tried to fight off the United States invasion. In 1851, Santa Anna went into exile in Kingston, Jamaica, and two years later, moved to Turbaco, Colombia. In April 1853, he was invited back by rebellious conservatives, with whom he succeeded in retaking the government. This reign was no better than his earlier ones. He funneled government funds to his own pockets, sold more territory to the United States (Gadsden Purchase), and declared himself dictator for life with the title "Most Serene Highness". The Ayutla Rebellion of 1854 removed Santa Anna from power. Despite his generous payoffs to the military for loyalty, by 1855 even conservative allies had had enough of Santa Anna. That year a group of liberals led by Benito Juárez and Ignacio Comonfort overthrew Santa Anna, and he fled back to Cuba.

As the extent of his corruption became known, he was tried in absentia for treason; all his estates were confiscated by the government. Santa Anna lived in exile in Cuba, the United States, Colombia, and St. Thomas. In 1869, 74-year-old Santa Anna was living in exile in Staten Island, New York. He was trying to raise money for an army to return and take over Mexico City. During his time in New York City, he is credited with bringing in the first shipments of chicle, the base of chewing gum. He failed to profit from this, since his plan was to use the chicle to replace rubber in carriage tires, which was tried without success. Thomas Adams, the American assigned to aid Santa Anna while he was in the United States, experimented with chicle in an attempt to use it as a substitute for rubber. He bought one ton of the substance from Santa Anna, but his experiments proved unsuccessful. Instead, Adams helped to found the chewing gum industry with a product that he called "Chiclets". Santa Anna was a passionate fan of the sport of cockfighting. He would invite breeders from all over the world for matches and is known to have spent tens of thousands of dollars on prize roosters.

In 1874 he took advantage of a general amnesty and returned to Mexico. Crippled and almost blind from cataracts, he was ignored by the Mexican government at the anniversary of the Battle of Churubusco. Two years later, Santa Anna died in Mexico City on June 21, 1876, penniless and heartbroken.