In 1731 the Spanish Crown sent 55 settlers from the Canary Islands to San Antonio. The cornerstone of the church was laid on May 11, 1738, and the church was dedicated in 1755. It is named for Ferdinand III of Castile and is described as one of the oldest active cathedrals in the United States.
James Bowie married Ursula de Veramendi at the church in 1831. During the Battle of the Alamo in 1836, Santa Anna reportedly hoisted a red no-quarter flag from the church tower.
Between 1868 and 1873 architect Francois P. Giraud had part of the nave and the bell tower torn down. The church was rebuilt with twin bell towers and a Gothic Revival nave and consecrated in 1873. Today a 24-minute light show called San Antonio: The Saga is projected on its front.