Mission San Cayetano del Tumacácori was established by Jesuits in 1691 in a location near a Sobaipuri settlement on the east side of the Santa Cruz River.

In 1752, the village was reestablished and in 1753 the church of the Mission San José de Tumacácori began construction at the present site on the west side of the Santa Cruz River.

Alejo García Conde, intendant-governor of Arizpe, officially granted the mission land to the resident O'odham in response to an 1806 petition.

A small O'odham community continued to live and farm on the mission, until an 1848 Apache attack killed nine of them and the survivors abandoned the site.

[4]: 99–104 The mission is now part of the 360 acres (1.5 km2) of Tumacácori National Historical Park, which contains three separate sections and is open to the public daily.