The first Spaniards came to Presidio in 1535, when Álvar Núñez Cabeza de Vaca and his three companions stopped at the Indian pueblo, placed a cross on the mountain side, and called the village La Junta de las Cruces. On December 10, 1582, Antonio de Espejo and his company arrived at the site and called the pueblo San Juan Evangelista. By 1681 the area of Presidio was known as La Junta de los Ríos, or the Junction of the Rivers, for the Río Conchos and the Rio Grande join at the site. About 1760 a penal colony and a military garrison of sixty men were established near Presidio. In 1783 Juan Sabeata, the chief of the Jumano Indian nation, reported having seen a fiery cross on the mountain at Presidio. The settlement then became known as La Navidad en Las Cruces.

In 1830 the name of the area around Presidio was changed from La Junta de los Rios to Presidio del Norte. White settlers came to Presidio in 1848 after the Mexican War. Among them was John Spencer, who operated a horse ranch on the United States side of the Rio Grande near Presidio. Ben Leaton and Milton Faver, former scalp hunters for the Mexican government, built private forts in the area. The handful of Anglo settlers who came to the region were assimilated into the Hispanic population and their descendants are primarily Spanish speakers today.

During the Mexican Revolution, General Pancho Villa often used Ojinaga as his headquarters for operations and visited Presidio on numerous occasions.

In 1849 a Comanche raid almost destroyed Presidio, and in 1850 Indians drove off most of the cattle in town. A post office was established at Presidio in 1868, and the first public school was opened in 1887. In 1930 the Kansas City, Mexico and Orient Railway reached Presidio, and the town incorporated. The population grew from ninety-six in 1925 to 1,671 in 1988, but the number of businesses declined from seventy in 1933 to twenty-two in 1988. At the end of 1988 Presidio experienced a population boom due in part to previously undocumented aliens enrolled in the amnesty program. The population in 1990 was 3,422.