The city of Tijuana is situated in a region once inhabited by the Kumeyaay Indians, a tribe of Yuman-speaking hunter-gatherers. Europeans first arrived in 1542, when the Portuguese/Spanish explorer João Rodrigues Cabrilho toured the coastline of the area, which was later mapped in 1602 by Sebastián Viscaíno. In 1769, Father Juan Crespí documented more detailed information about the area that would one day be called the Valley of Tijuana and Father Junípero Serra founded the first mission of Alta California in San Diego.

More settlement of the area took place near the end of the mission era when José María Echendía, governor of the Baja California and Alta California, awarded a large land grant to Santiago Argüello in 1829. This large cattle ranch, Rancho Tía Juana ("Aunt Jane Ranch"), covered 100 sq km.

In 1848, as a result of the Mexican-American war with the United States, Mexico lost all of Alta California. Tijuana acquired a new and distinct character and purpose on the international border. The city began to shed its cattle ranching origins and began to play in a new role, forming a socio-economic structure for the city.