The sixteenth in the chain of missions, San Miguel was founded on July 25, 1797 by Padre Fermin Francisco de Lasuen, who was a successor of Padre Junipero Serra, as Presidente of the missions. Almost two years earlier, the site was selected for the mission to be named for the "Most Glorious Prince of the Celestial Militia, Archangel Saint Michael."

Three other missions were founded in 1797: San Jose (June 11), San Juan Bautista (June 24) and San Fernando (September 8). San Miguel was intended to fill in the space between Mission San Luis Obispo de Tolosa and Mission San Antonio de Padua.

By 1806, more than one thousand neophytes were living and working at Mission San Miguel. The success of the mission was largely due to Padre Juan Martin (1770 -1824).

From the church building, the property extended 18 miles to the north and 18 miles to the south; the property extended 66 miles to the east, and as far as the Pacific Ocean, 35 miles to the west.

The credit for taking advantage of the hot sulfur springs, nine miles to the south, goes to Padre Juan Cabot , who served San Miguel from October 1, 1807 until March 12, 1819; during his second period of service (November 7, 1824 to November 25, 1834) he had a shelter constructed at the hot springs. The Salinas Valley was just coming out of a 500-year epoch of cold, very moist climate. Rheumatoid arthritis was a common complaint of the natives. Padre Cabot saw that bathing in the hot sulfur springs was necessary to alleviate their suffering.

The mission was secularized in 1834; by 1841, there were only 30 Indians at the mission. The property was sold, by the last Mexican governor, in 1846; not until 1859 was the church proper returned to the Catholic Church. Franciscan friars have been in residence since 1928, and there is a novitiate at Mission San Miguel today.