Father President Fermin de Lasuen founded Mission San Miguel on July 25, 1797. Situated along the El Camino Real between Missions San Antonio and Mission San Luis Obispo, the mission site was established next to a large Salinan Village known as Cholam or Cholami. Fr. Buenaventura Sitjar, the first administrator at Mission San Miguel had ministered to the Salinan people for 25 years at Mission San Antonio prior to his arrival at Mission San Miguel. Fr. Sitjar was fluent in the Salinan language and baptized 25 youth the first day Mission San Miguel was established.

A temporary church was built in 1797 but was lost to fire in 1806 and preparation for a new adobe church began soon after. Tiles and adobe blocks were made and stored for 10 years before the stone foundation of the church was completed in 1816. By 1821 the entire church was completed along with the interior frescos designed by Esteban Munras.

Following Mexico's move to independence, mission life began to change. Mission San Miguel was secularized in 1834 and put under the control of a civilian administrator. With the exile of the Spanish Franciscans, the Salinan people left Mission San Miguel for their ancestral homelands throughout the Central Coast.

On July 4, 1846, Petronillo Rios and William Reed took possession of the mission Buildings and the Reed family occupied the recently abandoned mission. Following the murder of 11 Reed family members and household staff, the mission rooms were converted to commercial stores such as, a hotel, saloon, and retail shops.

President Buchanan returned the mission buildings and surrounding property to the Catholic Church in 1859. A resident priest was assigned to Mission San Miguel in 1878 and the mission parish was established.

In 1928 the mission was returned to the Franciscans, becoming a novitiateor training school for those becoming Franciscan Friars, as it remains today. The Franciscans have carried on with continued restoration, always keeping the integrity of the historic structures. The mission visitor enters a church virtually unchanged since it was built. The wall decorations have had little or no restoration treatment or modification. The more recent buildings associated with the mission were built using historic adobe materials and methods.

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.