San Cayetano del Tumacácori Mission was established in 1691 by Father Eusebio Francisco Kino. It was established one day before the Guevavi Mission, making it the oldest Jesuit mission site in southern Arizona. The mission was originally called San Cayetano del Tumacácori and was located in a different location than the National Monument. It was established at an extant native O’odham or Sobaipuri settlement on the east side of the river. The location of this Sobaipuri settlement and the original place visited by Kino has been identified by archaeologist Deni Seymour who excavated and reported on the original San Cayetano del Tumacacori mission site, revising the earlier opinions of Charles Di Peso as to where this settlement was located.
After the Pima rebellion of 1751, the mission was moved to the present site on the west side of the Santa Cruz river and renamed San José de Tumacácori. By 1848, the mission was abandoned and began falling into severe disrepair. Preservation and stabilization efforts began in 1908 when the area was declared a National Monument by President Theodore Roosevelt and continue today.