Ysleta, now part of the city of El Paso, is perhaps the oldest town in Texas. The Pueblo Revolt of 1680 drove Spanish colonists, Franciscan missionaries, and Pueblo and Tigua Indians from northern New Mexico to the Paso del Norte. At a site of the south bank of the Rio Grande, some twelve miles from today's downtown El Paso, the settlement of Santisimo Sacramento - later to be called Ysleta del Sur - was established by the refugees. Temporary quarters were soon constructed. The new Ysleta del Sur ("little island of the south") was located a league and a half east of Guadalupe Mission at the site of present Ciudad Juárez, Chihuahua. The first Mass in the area was celebrated near Ysleta on October 12, 1680.

Work on a permanent mission did not begin until two years later when a failed re-colonization expedition to northern New Mexico by the Spanish brought additional refugees to Paso del Norte. Completed in 1692 the Spanish named the new structure Corpus Christi de la Isleta del Sur. It provided tranquil sanctuary for religious worshipers for almost the next fifty years until the flood waters of the Rio Grande washed it away in 1740. Not to be discouraged, the settlers began construction of a new structure on the same site. It was completed in 1744 and named San Antonio de la Ysleta, named for Saint Anthony, the patron saint of the Tigua Indians.

The mission's name has been changed several times, most recently to Our Lady of Mount Carmel. Between 1829 and 1831 the Rio Grande cut a new channel, which placed Ysleta on an island formed by the old and new channels. When the deepest channel became the international boundary in 1848, Ysleta became part of the United States. An election in 1880 approved incorporation, and in 1889 the town council declared Ysleta a city. After a stormy period of squabbles over water supply, land grants, limited resources, and other issues, the town government dissolved in 1895.

By an election in 1873 Ysleta replaced San Elizario as the El Paso county seat. But the coming of the railroads in 1881 changed the population center of the county, and in 1883 a strongly disputed election made El Paso the county seat. A bridge was built across the Rio Grande in 1929 linking Ysleta with Zaragosa, Chihuahua. This crossing point has been increasingly important in recent years, since the introduction of numerous maquiladoras in the area. In 1955 El Paso annexed Ysleta, although residents of the smaller town had voted against the move. The annexation was upheld by the United States Supreme Court. Ysleta Independent School District, under a 1953 law, was allowed to retain its identity. The Tiguas, who helped the United States military as scouts during the Indian wars, were recognized as a tribe by the state of Texas in 1967 and by the United States Congress in 1968. As a result, they have established a housing area and various business enterprises on their reservation in the oldest part of Ysleta.