St. Mary's College began in 1863 as a diocesan college for boys established by the Most Rev. Joseph Alemany, a member of the Order of Preachers and the first archbishop of San Francisco. Unhappy with the archdiocese's operation of the college, Archbishop Alemany applied for assistance from Rome and in 1868 St. Mary's College was handed over to the De La Salle Christian Brothers.
In 1889, the college moved east across San Francisco Bay to Oakland, California. The location on the corner of 30th and Broadway became affectionately known as "The Brickpile" and Saint Mary's College would call Oakland home until 1928, when it moved further eastward to Moraga after a fire severely damaged the Brickpile. The Oakland site is California Historical Landmark #676 and is marked by a commemorative plaque. The former San Francisco site is now the site of the St. Mary's Park neighborhood. The college and high school sections separated not long after the move to Moraga and the high school is currently located in Albany.
During its first years in Moraga, the college nearly went bankrupt, but eventually managed to gain financial security when it was bought by Archbishop John Joseph Mitty, for whom a residence hall is now named. During World War II the college was used by the United States Navy for the training of pilots. Former President Gerald Ford was briefly stationed at the school and served as a naval instructor. The navy erected many buildings, including the world's largest indoor pool, but only one, Assumption Hall, remains on the campus as the school had little use for most of the buildings after the war. Saint Mary's continued to be a male-only school until 1970, when it became coeducational. Since then, more women have come to the college and by 2011, 62% of the students were women.
In the 1970s the college was well known by secondary schools throughout the San Francisco Bay Area for producing the Saint Mary’s Math Contest. The popular contest was discontinued in 1978 but later became the chief inspiration for the Julia Robinson Mathematics Festival which continues to this day.
There are still roughly two dozen Christian Brothers living and working at the school, and the school presidents had always been Brothers until 2013. Recognizing the dwindling number of Christian Brothers, in 2003 the college's bylaws were changed to allow the election of a non-Christian Brother to the presidency if no qualified Brother exists or steps forward. James A. Donahue, a committed and engaged Roman Catholic, became the first non-Christian Brother to serve as president in the 150-year history of Saint Mary’s on July 1, 2013.