Built by order of Viceroy Martín Enríquez de Almanza in 1576, this building that now houses the Historic Museum of the Sierra Gorda was originally a prison and military fort. The fort was used by Spanish colonialists in their settling of an area occupied by semi-nomadic, warring indigenous peoples like the Pame and Jonaces, whose attacks lead to the fort having to be rebuilt at the end of the 16th century under supervision of Luis Carbajal y de la Cueva.

Owing to their semi-nomadic, warring culture, the indigenous people of the region were among the last to be heavily targeted for Catholic evangelization. Five Franciscan Missions were built for this purpose across the Sierra Gorda , with the oldest of them located across the street from this Museum, in the town of Jalpan de Serra.

All five are now part of a UNESCO World Heritage Site, and this museum includes reproductions of their facades as well as of the austere accommodations they provided to missionaries and indigenous converts alike. The modern-day use of the building as a museum dates from 1991, when it opened to display items related to the indigenous people, the history of colonialism and the Franciscan Missions, as well as of contemporary life in the region.