The inhabitants of the Sierra de San Borja when first visited by Jesuit Catholic missionaries early in the 18th century were Cochimí Indians, nomadic hunter-gatherers.

At their most active in the 1760s, each of the missions attracted about 1,700 Cochimí as temporary residents, but those numbers were unsustainable and introduced European diseases rapidly caused a decline in the Indian population.

In explorations in the 1970s, author Harry W. Crosby found six major sites of Great Mural rock art southeast of the San Borja mission.

[5] The paintings of the Great Mural rock art of the Sierra de San Borja are smaller than more southerly works, less diverse in their subject matter, and are always colored in shades of red.

[7] The Sierra de San Borja and neighboring mountain ranges are recognized as a Priority Region for the Conservation of Biodiversity by the government of Mexico.