Humans have inhabited the valleys for at least 8000 years. The Santamariano culture thrived in the valleys from approximately 1000 and 1480 AD. The period saw a growth in population and irrigated agriculture, with towns and villages on the main valley floor and along the western tributary streams. The Ruins of Quilmes in Tucumán Province may have housed about 5000 people at the settlement's peak. The valleys were conquered by the Inca Empire between 1470 and 1480. The valleys were part of the empire's southeastern Qullasuyu province. The Inca extended their road network through the region, and built fortresses and mountaintop shrines. Food crops grown in the valleys included maize, Chenopodium, tubers, beans, and chili peppers (Capsicum). Manufacturing activities in the valley included copper and gold metallurgy, marine shell, mica, obsidian, stone beads, and ceramics.[1]

The Spanish conquered the Inca Empire in the 1530s, and by 1543 Inca control of the valleys had collapsed. The people of the region resisted Spanish conquest until 1650.[1] Tribes of the area included the Calchaquíes, Tafí, and the Yokavil (Santa María).