It was part of Spain's effort to colonize the region, and convert the Timucuan and Apalachee Indians to Christianity.

The site where the original mission stood was added to the U.S. National Register of Historic Places on May 14, 1971.

San Damián de Cupaica was founded in 1639, the third Spanish mission in Apalachee Province.

San Damián survived James Moore's invasion of Apalachee Province in January 1704, but was captured by Creek warriors in June 1704.

[2] A later mission named San Joseph de Escambe was established in 1741 at the present-day community of Molino, Florida along the Escambia River north of Pensacola, lending its name both to the river and later to Escambia County, Florida.