The City of San Antonio is one of the oldest Spanish settlements in Texas and was, for decades, its largest city. Before Spanish colonization, the site was occupied for thousands of years by varying cultures of indigenous peoples. The historic Payaya Indians were likely those who encountered the first Europeans.

The "Villa de Bejar" was founded by Spanish explorers on May 5, 1718, by then Governor Martin Alarcon, at the headwaters of the San Pedro Creek. San Antonio's history is closely tied to Mexico because it was part of the Spanish Empire and the Mexican Republic. The mission San Antonio de Valero was established on the east bank of the creek and a presidio was 3/4 of a league downstream. Development of the Spanish colonial city followed. A trading post was also established near the presidio and the town developed as the capital of Tejas, a province of colonial Spain. It was the northernmost settlement associated with the Hispanic culture of the Valley of Mexico.

After Mexico achieved independence in 1821, Anglo-American settlers entered the region from the United States. In 1836, Anglo-Americans gained control of Texas in the fighting that gained independence for the Republic of Texas. In 1845 Texas was annexed by the United States, and became a state.

After thousands of years of succeeding indigenous cultures, the historic Payaya Indians coalesced as a distinct ethnic group. They lived near the San Antonio River Valley, in the San Pedro Springs area, which they called Yanaguana, meaning “refreshing waters”.

In 1536, Álvar Núñez Cabeza de Vaca, a shipwrecked Spanish explorer who was enslaved by Native Americans for a period, visited the interior of what would later be called Texas. He saw and described the river later to be named the San Antonio. He eventually rejoined Spanish colleagues in Mexico City.

Several expeditions to the region of Texas, an area of great strategic importance to the Spanish crown, were organized from the Convent of Querétaro. With that goal in 1675, an expedition formed by Fray Antonio de Olivares, Fray Francisco Hidalgo, Fray Juan Larios and Fernando Orozco Josué Hernández y hay hete suéter is Natalia Orozco, were sent to explore and recognize the country beyond the borders of the Rio Grande, to test the possibilities of new settlements in the area.

In 1691, a group of Spanish explorers and missionaries came upon the river and Native American settlement (located in the area of present-day La Villita) on June 13. As it was the feast day of Saint Anthony of Padua, Italy, they named the place and river San Antonio in his honor.

In 1709, the expedition headed by Pedro de Aguirre, together with Fray Antonio de Olivares and Fray Isidro de Espinosa was undertaken which consisted of exploration of the territory where the present city of San Antonio is located and extended to the Colorado River. The same year he traveled to Spain to convince the authorities to establish and maintain new missions on the bank of the San Antonio River at the present-day city of San Antonio.