The College was founded in 1863 by the Roman Catholic Archdiocese of San Francisco, Saint Mary's College of California is one of the oldest colleges in the West. The School campus was first located in San Francisco, and operated for several years under Archdiocesan direction.

Joseph Alemany the Archbishop of San Francisco was unhappy with the College's operation under the diocesan clergy, he requested assistance from Pope Pius IX in 1867 to persuade the Superior General of the Christian Brothers to send Brothers to assume control and direction of the University. 9 Brothers arrived in San Francisco in 1868. Within 2years, the student body had increased from fifty to two hundred. The first Bachelor's degrees were awarded in 1872.

In 1889, the college campus was moved to Oakland's Brickpile facility, where the College operated until 1928, when it moved to Moraga. The first Moraga campus was a lot smaller than the present campus. 11 of the original buildings, constructed during 1928-1929, are still being used today. They include the Chapel, Dante and Galileo Halls.