The new settlement (part of a chain of Spanish missions) was named for a 15th-century theologian and warrior priest who resided in the Abruzzo region of Italy.

Around 1760, construction of a larger church building begun on the east side of the Mission compound, but was never completed due to the lack of sufficient labor.

Some 265 neophytes resided in adobe huts at the Mission in 1756; by 1790 the native Coahuiltecan people were living in stone quarters, though their number had dropped to 58.

The Mission often encountered systemic issues concerning corralling the native's nomadic tendencies, which consequently led to large amounts of the converted Indians to sporadically leave.

[3] Members of the Claretian and Redemptorist Orders also held mass in the church until 1967, when the Franciscans returned to Mission San Juan.

Three Spanish Colonial-period statues that sat at the altar were stolen sometime on the night of Monday, July 31 or early the morning of Tuesday, August 1, 2000.