It came into being as part of Saint Mary's College of California, founded in 1863 by the Catholic Church, and put under the auspices of the Institute of the Brothers of the Christian Schools in 1868.

In 1853, Joseph Sadoc Alemany was named Archbishop of San Francisco and immediately began to work to strengthen the fledgling system of Catholic education that existed at the time.

Among his goals was the establishment of an educational institution for young men with an eye to fostering a home-grown clergy he felt was necessary for the survival of the Church in California.

The Brothers faced formidable difficulties, including financial problems, poor teaching conditions, low enrollment, an earthquake, and an outbreak of smallpox.

It was a difficult time for the school; enrollment was declining, De La Salle Hall was gone, leaving minimal facilities to accommodate 475 students.

In his assignment to Saint Mary's, Brother Norman had been given a mandate to “close it up or build it up!” The school community chose transformation.

“The possible demise of Saint Mary’s and its embodiment of the Lasallian vision,” Brother Norman reflected years later, “was simply an unacceptable option.” Work began on a facilities master plan and a major fundraising campaign.

In August 1995, after 132 years as an all-male school, a 55/45 percent mix of young men and women entered the freshman class, and twenty-two sophomore girls joined ninety-eight male classmates.

As Saint Mary's marked its 75th year on the Berkeley campus in 2002, Frates Memorial Hall opened, providing eight new classrooms and an amphitheater, gift of Dr. and Mrs. Frank E. Frates Jr., Class of 1927, and donors to the school's successful Creating Futures campaign for the new building and tuition assistance endowment funds.

As of the end of the 2010 cross country season, the boys were attempting to achieve their 25th consecutive league championship and the girls won 13 of the last 15 titles since the school's transition to coeducation in 1995.

Most live productions take place in the Saint Mary's auditorium, colloquially known as "the O-ditorium" in commemoration of long-time theater instructor Antone Olivier.