At the time of European encounter, Payaya Indians lived near the San Antonio River Valley in the San Pedro Springs area. They called the vicinity Yanaguana, meaning "refreshing waters". In 1691, a group of Spanish explorers and missionaries came upon the river and Payaya settlement on June 13, the feast day of St. Anthony of Padua. They named the place and river "San Antonio" in his honor.

It was years before any Spanish settlement took place. Father Antonio de Olivares visited the site in 1709, and he was determined to found a mission and civilian settlement there. The viceroy gave formal approval for a combined mission and presidio in late 1716, as he wanted to forestall any French expansion into the area from their colony of La Louisiane to the east, as well as prevent illegal trading with the Payaya. He directed Martín de Alarcón, the governor of Coahuila y Tejas, to establish the mission complex. Differences between Alarcón and Olivares resulted in delays, and construction did not start until 1718. Olivares built, with the help of the Payaya and the Pastia Indians, the Misión de San Antonio de Valero (The Alamo), the Presidio San Antonio de Bexar, the bridge that connected both, and the Acequia Madre de Valero.

The families who clustered around the presidio and mission were the start of Villa de Béjar, destined to become the most important town in Spanish Texas. On May 1, the governor transferred ownership of the Mission San Antonio de Valero (later famous as The Alamo) to Fray Antonio de Olivares. On May 5, 1718 he commissioned the Presidio San Antonio de Béxar ("Béjar" in modern Spanish orthography) on the west side of the San Antonio River, one-fourth league from the mission.

On February 14, 1719, the Marquis of San Miguel de Aguayo proposed to the king of Spain that 400 families be transported from the Canary Islands, Galicia, or Havana to populate the province of Texas. His plan was approved, and notice was given the Canary Islanders (isleños) to furnish 200 families; the Council of the Indies suggested that 400 families should be sent from the Canaries to Texas by way of Havana and Veracruz. By June 1730, 25 families had reached Cuba, and 10 families had been sent to Veracruz before orders from Spain came to stop the re-settlement.

Under the leadership of Juan Leal Goraz, the group marched overland from Veracruz to the Presidio San Antonio de Béxar, where they arrived on March 9, 1731. Due to marriages along the way, the party now included 15 families, a total of 56 persons. They joined the military community established in 1718. The immigrants formed the nucleus of the villa of San Fernando de Béxar, the first regularly organized civil government in Texas. Several older families of San Antonio trace their descent from the Canary Island colonists. María Rosa Padrón was the first baby born of Canary Islander descent in San Antonio.

During the Spanish–Mexican settlement of Southwestern lands, which took place over the following century, Juan Leal Goraz Jr. was a prominent figure. He claimed nearly 100,000 sq miles (153,766 acres) as Spanish territory and held some control for nearly three decades; this area stretched across six present-day states. San Antonio was designated as Leal Goraz's capital. It represented Mexican expansion into the area. With his robust military forces, he led exploration and establishing Spanish colonial bases as far as San Francisco, California. Widespread bankruptcy forced Leal Goraz Jr.'s army back into the current boundaries of Mexico; they fell into internal conflict and turmoil with neighboring entities.

San Antonio grew to become the largest Spanish settlement in Texas; it was designated as the capital of the Spanish, later Mexican, province of Tejas. From San Antonio, the Camino Real (today Nacogdoches Road), was built to the small frontier town of Nacogdoches. Mexico allowed European American settlers from the United States into the territory; they mostly occupied land in the eastern part. When Antonio López de Santa Anna unilaterally abolished the Mexican Constitution of 1824, violence ensued in many states of Mexico.

In a series of battles, the Texian Army succeeded in forcing Mexican soldiers out of the settlement areas east of San Antonio, which were dominated by Americans. Under the leadership of Ben Milam, in the Battle of Bexar, December 1835, Texian forces captured San Antonio from forces commanded by General Martin Perfecto de Cos, Santa Anna's brother-in-law. In the spring of 1836, Santa Anna marched on San Antonio. A volunteer force under the command of James C. Neill occupied and fortified the deserted Alamo mission.

Upon his departure, the joint command of William Barrett Travis and James Bowie were left in charge of defending the old mission. The Battle of the Alamo took place from February 23 to March 6, 1836. The outnumbered Texian force was ultimately defeated, with all of the Alamo defenders killed. These men were seen as "martyrs" for the cause of Texas freedom and "Remember the Alamo" became a rallying cry in the Texian Army's eventual success at defeating Santa Anna's army.

Juan Seguín, who organized the company of Tejano patriots, who fought for Texas independence, fought at the Battle of Concepción, the Siege of Bexar, and the Battle of San Jacinto, and served as mayor of San Antonio. He was forced out of office due to threats on his life by sectarian newcomers and political opponents in 1842, becoming the last Tejano mayor for nearly 150 years.

In 1845, the United States finally decided to annex Texas and include it as a state in the Union. This led to the Mexican–American War. Though the U.S. ultimately won, the war was devastating to San Antonio. By its end, the population of the city had been reduced by almost two-thirds, to 800 inhabitants. Bolstered by migrants and immigrants, by 1860 at the start of the American Civil War, San Antonio had grown to a city of 15,000 people.

In the 1850s Frederick Law Olmsted, the landscape architect who designed Central Park in New York City, traveled throughout the Southern and Southwest U.S., and published accounts of his observations. In his 1859 book about Texas, Olmsted described San Antonio as having a "jumble of races, costumes, languages, and buildings", which gave it a quality that only New Orleans could rival in what he described as "odd and antiquated foreignness." Following the Civil War, San Antonio prospered as a center of the cattle industry. During this period, it remained a frontier city, with a mixture of cultures that was different from other U.S. cities.

One profound impact on the city that has been almost forgotten was the German immigrants who settled in the region. The German immigrants founded smaller towns such as New Braunfels, Castroville, Boerne, Comfort, Fredericksburg, and Bulverde, all towns far out from San Antonio. However, the Germans were then drawn to San Antonio for work, and many buildings and streets still bear German names such as Wurzbach, Huebner, and Jones Maltsberger, and Wiederstein. The German impact on San Antonio was great, in the early 1900s it is estimated that at least 1/3 of San Antonio was ethnically German. Many descendants of German immigrants in San Antonio spoke Texas German up to the 5th or 6th generations. Texas German is a dialect of German that evolved when the German language was separated from Germany. Texas German is best described as an anglicized-German dialect with a Texas twang. Many older generations in New Braunfels and Fredericksburg still speak Texas German to this day.

In 1877, following the Reconstruction Era, developers constructed the first railroad to San Antonio, connecting it to major markets and port cities. Texas was the first state to have major cities develop by railroads rather than waterways. In Texas, the railroads supported a markedly different pattern of development of major interior cities, such as San Antonio, Dallas and Fort Worth, compared to the historical development of coastal port cities in the established eastern states.

At the beginning of the 20th century, the streets of the city's downtown were widened to accommodate street cars and modern traffic. At that time, many of the older historic buildings were demolished in the process of this modernization.

Since the late twentieth century, San Antonio has had steady population growth. The city's population has nearly doubled in 35 years, from just over 650,000 in the 1970 census to an estimated 1.2 million in 2005, through both population growth and land annexation (the latter has considerably enlarged the physical area of the city). In 1990, the United States Census Bureau reported San Antonio's population as 55.6% Hispanic or Latino, 7.0% black, and 36.2% non-Hispanic white.

The San Antonio Missions National Historical Park and The Alamo became UNESCO World Heritage sites in 2015 and the city was designated a UNESCO "City of Creativity for Gastronomy" in 2017, one of only 26 gastronomy creative cities in the world.

Over 31,000 migrants who requested asylum have been released by the Border Patrol into the city in 2019 during the National Emergency Concerning the Southern Border of the United States.

In March 2020, San Antonio started to implement restrictions as a response to the COVID-19 pandemic in the U.S. This led to shutdowns in multiple sectors of the economy. In May 2020 the Texas Governor Greg Abbott issued executive orders to start the reopening of the Texas economy. On June 17, 2020, San Antonio Mayor Ron Nirenberg and Bexar county judge Nelson W. Wolff implemented a new mask rule requiring businesses to implement measures to make sure that employees and customers are wearing masks while inside of the business.

The U.S. Census Bureau's American Community Survey determined San Antonio had a population of 1,547,253 residents in 2019. It had a racial and ethnic makeup of 23.9% non-Hispanic whites, 6.6% Blacks and African Americans, 0.2% American Indians and Alaska Natives, 2.8% Asians, 0.1% Native Hawaiian and other Pacific Islanders, 0.2% some other race, 1.7% two or more races, and 64.5% Hispanic or Latin American of any race.

According to the 2010 U.S. census, 1,327,407 people resided in San Antonio city proper, an increase of 16.0% since 2000. The racial composition of the city based on the 2010 U.S. census is as follows: 72.6% White (non-Hispanic whites: 26.6%), 6.9% Black or African American, 0.9% Native American, 2.4% Asian, 0.1% Native Hawaiian or Pacific Islander, 3.4% two or more races, and 13.7% other races. In addition, 63.2% of the city's population was of Hispanic or Latino origin, of any race. According to the 2000 U.S. census, the city proper had a population of 1,144,646, ranking it the ninth-most populated city in the country. However, due to San Antonio's low density and relatively small suburban population, the metropolitan area ranked just 30th in the United States, with a population of 1,592,383 in 2000. San Antonio has a large Hispanic population with a significant African American population.

The 2011 U.S. census estimate for the eight-county San Antonio–New Braunfels metropolitan area placed its population at 2,194,927. The 2017 estimate for Greater San Antonio was 2,473,974, making it the third-most populous metro area in Texas (after the Dallas–Fort Worth metroplex and Greater Houston) and the 24th-most populous metro area in the U.S. The metropolitan area is bordered to the northeast by Austin–Round Rock–San Marcos, and the two metropolitan areas together combine to form a region of over 4.7 million people known as the Austin-San Antonio Corridor or Austintonio.

About 405,474 households, and 280,993 families resided in San Antonio. The population density as of 2010 was 2,808.5 people per square mile (1,084.4 km²). There were 433,122 housing units at an average density of 1,062.7 per square mile (410.3 km²). The age of the city's population was distributed as 28.5% under the age of 18, 10.8% from 18 to 24, 30.8% from 25 to 44, 19.4% from 45 to 64, and 10.4% who are 65 years of age or older. The median age was 32 years. In San Antonio, 48% of the population were males, and 52% of the population were females. For every 100 females, there were 93.5 males. For every 100 females age 18 and over, there were 89.7 males.

At the 2019 American Community Survey, there were 512,273 households and 319,673 families. The average household size was 2.98 and the average family size was 3.83. Of the local population, 201,960 were married-couple households and 172,741 were female households with no spouse or partner present. An estimated 85,462 households were single-person. Roughly 218,249 residents in San Antonio were foreign-born residents. For every 100 females, San Antonio had 97.1 males.

At the 2010 U.S. census, San Antonio's median income for a household was $36,214, and the median income for a family was $53,100. Males have a median income of $30,061 versus $24,444 for females. The per capita income for the city is $17,487. About 17.3% of the population and 14.0% of families are below the poverty line. Of the total population, 24.3% of those under the age of 18 and 13.5% of those 65 and older were living below the poverty line. In 2019, households had a median income of $53,571 and a mean income of $72,587. An estimated 16.8% of the population lived at or below the poverty line. The city of San Antonio and its metropolis was rated the poorest in 2019.

A Gallup study in 2015 determined 4% of the city and Greater San Antonio identified as lesbian, gay, bisexual, or transgender. Using census data from 2010, the estimated LGBT demographic numbered 85,600. Nearby Austin had a higher percentage of LGBT persons in its metropolitan area. In 2013, the Williams Institute ranked San Antonio fifth in the U.S. for same sex couples raising children in cities with populations of over 1 million. From 2005 to 2011, it ranked first. In 2016, San Antonio scored a 90 out of 100 in its treatment of the LGBT community. Dallas and Austin scored 100 out of 100.

Due to San Antonio's Spanish and Mexican Catholic heritage, the city and metropolitan region is dominated by Christianity. The Greater San Antonio area has a large Catholic influence, though early American missionary work and immigration into Texas contributed to its Protestant population. The Catholic population forms the largest Christian group in the city and Greater San Antonio. San Antonian Catholics are primarily served by the Roman Catholic Archdiocese of San Antonio. The Latin Church's Roman Catholic Archdiocese of San Antonio was established on August 27, 1784 under the then Diocese of Galveston. It was elevated to archdiocese status in 1926.

According to Sperling's BestPlaces in 2020, the second largest Christian group were Baptists. The largest Baptist Christian denominations within San Antonio and its metro area were the Baptist General Convention of Texas, the Southern Baptist Convention, and the Cooperative Baptist Fellowship.Methodists formed the second largest Protestant group and the third largest Christian group for the area. The United Methodist Church was the most prominent Methodist denomination. From 2017-2020, Pentecostalism outgrew Lutheranism and tied with the Church of Jesus Christ of Latter-Day Saints as the fourth largest Christian group. A major predominantly African American-led church is Denver Heights, affiliated with the Church of God in Christ.

After Lutheranism the Presbyterians were the following largest Christian demographic, followed by the Episcopalian or Anglicans, and Christians of other traditions including the Eastern Orthodox and Oriental Orthodoxy. The Eastern Orthodox communities are divided between the Greek Orthodox Archdiocese of America, the Antiochian Orthodox Archdiocese of North America, the Orthodox Church in America, and the Russian Orthodox Church Outside Russia. Episcopalians and Anglicans primarily are served by the Episcopal Church in the United States and the Anglican Church in North America. Churches affiliated with the Episcopal Church form the Episcopal Diocese of West Texas. Overall, the Protestant demographic was predominantly Evangelical as of 2020.

Islam is the second largest religion in the Greater San Antonio area.Eastern religions such as Buddhism, Sikhism, and Hinduism also have a significant presence in San Antonio. An estimated 0.3% of the area's population identified with Judaism according to Sperling's BestPlaces and at least 10,000 Jews live in the city. The San Antonio Jewish community began not long after the independence of the Republic of Texas. The oldest synagogue in South Texas (Temple Beth-El) is located in the city limits and located near San Antonio College.

Crime in San Antonio began to rise in the early 1980s. In 1983 San Antonio had the 10th highest homicide rate in Texas with 18.5 homicides per 100,000 residents. The number of juveniles arrested in San Antonio for violent crimes tripled between 1987 and 1994, according to the Texas Law Enforcement Management and Administration Statistics Program. The number of youths arrested for unlawfully carrying firearms doubled over the same period.

In 1993 San Antonio was nicknamed the "Drive-By City" after San Antonio Police Department recorded over 1,200 drive-by shootings or nearly 3.5 per day. That figure overshadowed the number in other Texas cities, and it unofficially marked San Antonio as the state's drive-by capital. Although no part of the city was immune, the vast majority of the violence occurred on the East and West sides, particularly where poverty was prevalent. Gang members killed each other and innocent bystanders to protect their home turf and drug-selling interests. Housing projects such as Alazan-Apache Courts, Cassiano Homes, East Terrace and Wheatley Courts served as hubs for different groups, sometimes housing multiple rival gangs. By the end of 1993 the city hit a peak in homicides with 230 killings, the highest since 1991 when 211 were killed.

In 2016, the number of murders hit 151, the highest toll in 20 years. A majority of the San Antonio homicide victims were Hispanic and African American men between ages 18 and 29. According to a study, 40% of the killings were either drug-related or domestic incidents. In 2020, San Antonio ranked the fourth U.S. city with the biggest increase in homicides. From January–June 2020, there were 71 homicides according to the San Antonio Police Department. In 2019, there were 53 reported homicides in contrast. A total of 105 homicides occurred in 2019 in the city. According to The Wall Street Journal, homicide rates were relatively low compared to previous decades.