In 1731 settlers from the Canary Islands laid out the town of San Fernando de Béxar near the presidio, where a civilian community had been planned when the presidio and mission were established. During its early years the settlement suffered from raids by Apache and Comanche tribes. The mission was secularized in 1793 and became a military post. San Fernando de Béxar functioned as provincial capital from 1773 to 1824, but in subsequent years its political authority waned. By 1837, when it became a county seat of the Republic of Texas, it had been renamed San Antonio.

At the time of Mexican independence in 1821, San Antonio was, along with Goliad and Nacogdoches, one of three established Spanish communities in Texas. In the summer of that year, Stephen Austin (Austin, Stephen) arrived in the city (then seat of the Spanish government in Texas) to follow through on a permit obtained by his father for the admission of 300 U.S. families into the territory. In December 1835, at the outset of the Texas revolution, Texan forces occupied the Alamo. They remained there until March 1836, when they were massacred by Mexican troops under General Antonio López de Santa Anna (Santa Anna, Antonio López de) following a 13-day siege. The presidio ceased to exist with the independence of Texas in April.

In 1836 San Antonio was still the foremost city of Texas, with some 2,500 inhabitants. It grew rapidly after independence, led by large numbers of German immigrants. During the last decades of the 19th century, San Antonio, as the starting point for the Chisholm Trail, became a major cattle centre, where herds were assembled for the overland drives to the railheads in Kansas.

The city quickly became the commercial hub of the Southwest. The arrival of the first railroad in 1877 brought migrants from the American South, and Mexican immigrants settled there after the start of the Mexican Revolution in 1910. San Antonio was a major military centre during World Wars I and II, a factor that continued to dominate its economy in subsequent decades. In 1968 a world's exposition, known as HemisFair, was held there to commemorate the city's 250th anniversary and to celebrate its cultural ties with Latin America. In 1981 Henry Cisneros was elected the city's first Hispanic mayor since the mid-19th century; Cisneros served until 1989, and in 2001 Ed Garza was elected the city's second modern-era Hispanic mayor.

Military installations largely account for San Antonio's rapid growth after 1940. Fort Sam Houston (1879), inside the city, is the headquarters of the U.S. 5th Army and site of a national cemetery and the Academy of Health Sciences, the army's basic school for medical personnel. Nearby are three U.S. Air Force bases: Lackland, Randolph, and Brooks. Lackland, in the southwestern part of the city, is a training base for recruits. Randolph, in a suburban area to the northeast, is headquarters of the Air Education and Training Command. Brooks, in the southeastern part of the city, is the site of the School of Aerospace Medicine. The region's first air base, Kelly (established 1917), was closed in 2001, and its site was redeveloped for business use.

In addition to the military, major components of San Antonio's economy are education, health care and medical research, business and financial services, and—most importantly—tourism. Manufactures include aerospace equipment, textiles, semiconductors, industrial machinery, and shoes; there are also oil refineries. Agricultural production in the area includes cattle, poultry, peanuts (groundnuts), sorghum, vegetables, and greenhouse plants; the processing of and research on agricultural products is also important. A large portion of trade between Mexico and the United States passes through the San Antonio area's interstate highway system. The city also has an international airport.

San Antonio is the seat of St. Mary's University (1852), Trinity University (1869), University of the Incarnate Word (1881), Our Lady of the Lake University (1896), St. Philip's College (1898), San Antonio College (1925), and the University of Texas (Texas, University of) at San Antonio (1969). A health science centre of the University of Texas is also there.

HemisFair Park, the site of the world's fair, is linked to the central city by the River Walk and is used for conventions and exhibitions; the park's Institute of Texan Cultures traces nationalities of Texas, and its Tower of the Americas, 750 feet (229 metres) tall, is a city landmark. San Fernando Cathedral (completed 1873) is the seat of a Roman Catholic archbishopric. The Marion Koogler McNay Art Museum contains a notable collection of modern French paintings, and the Witte Museum houses Texas artifacts. The San Antonio Museum of Art has a collection of Latin American art, and the Museo Alameda, which is affiliated with the Smithsonian Institution, is dedicated to Latin American culture. The city also has dozens of music, dance, and theatre organizations, including a professional symphony. SeaWorld (SeaWorld, Inc.) San Antonio includes amusement rides and animal shows as well as marine animal exhibits. The Alamodome (1993) is the site of conventions and concerts and the home of the city's professional basketball team, the Spurs. The San Antonio Zoo (San Antonio Zoological Gardens and Aquarium), which includes an aquarium, is a popular attraction. Annual events include a rodeo (February), Fiesta San Antonio (April), and the Texas Folklife Festival (June).