When the Spanish came, Southern Arizona was heavily populated by Pima, Tohono O'Odham and Sobaipuri Indians. They lived in numerous villages along the flowing rivers of that day, especially the Santa Cruz River which runs north from Mexico through the heart of Southern Arizona. The Spanish introduced cattle, horses and Christianity and established military presidios in several places, including Tubac and Tucson. The Indians controlled their lands although the Spanish organized united military expeditions against the Apaches and others from time to time using thousands of Pima and Sobaipuri braves as allies.

Then, in 1736 a Yaqui Indian made a rich silver find at a place called Arizonac by the Spanish, just southwest of what is now Nogales. The name Arizonac may derive either of Tohono O'Odham words ali shonak (little spring) or the Basque words arritza onac (good or valuable rocky place).

The find was so rich, chunks of silver just laying around on the surface, that there was lengthy litigation over whether it was treasure (50% went to the king) or mine (20% went to the king). Arizonac came to be synonymous for quick riches and many prospectors and settlers moved north.

The Pima Indians who occupied much of southern Arizona resisted the new settlers and the Pima Revolt of 1751 pushed the Spanish out. This resulted in a military fort, a Presidio, being constructed in 1753 at what is now Tubac, although it was first called San Ignacio. A mission was established as well. Within a short time there were several hundred residents.

The Presidio was moved north to Tucson in 1776, leaving the residents without protection from hostile Indians and the settlement declined.