In 1659 Fray García de San Francisco founded Nuestra Señora de Guadalupe Mission, which still stands in downtown Ciudad Juárez, the oldest structure in the El Paso area. The Pueblo revolt of 1680 sent Spanish colonists and Tigua Indians of New Mexico fleeing southward to take refuge at the Pass. By 1682 five settlements were founded south of the river-El Paso del Norte, San Lorenzo, Senecú, Ysleta, and Socorro, thus providing the Pass with a concentration of population from that time to the present. The area became a trade center on El Camino Real del Tierra Adentro, or Royal Road of the Interior, which led from Mexico City to Santa Fe. Agriculture flourished, particularly the vineyards, producing fine wine and brandy.

When Mexico won its independence from Spain in 1821 the El Paso area and what is now the American Southwest became a part of the Mexican nation. The Treaty of Guadalupe Hidalgo of February 2, 1848, fixed the boundary between the two nations at the Rio Grande, and thus El Paso del Norte, the future Ciudad Juárez, became a bordertown.

During the period of the French intervention in Mexico the republican cause under the leadership of President Benito Juárez took refuge in El Paso del Norte in August 1865 and governed from there for almost a year. The tide began to turn in favor of the Juárez republicans, who returned to Mexico City in triumph in 1867. On September 16, 1888, El Paso del Norte was renamed Ciudad Juárez after the Mexican hero.