STPSU was founded in 1898 by San Francisco Archbishop Patrick William Riordan with a faculty from the Sulpician order.

The board of trustees includes the Archbishop of San Francisco, Salvatore Cordileone, six bishops from dioceses in California, Washington State, and Hawaii, and other clergy.

The seminary was staffed by the Society of Saint Sulpice in France, which provided three French and two American priests.

Riordan named the new seminary after Saint Patrick of Armagh to honor the Irish donors to the project.

[3][4][5] On August 24, 1898, St. Patrick's Seminary was dedicated by Riordan, joined by Bishops George Montgomery of Los Angeles and Thomas Grace of Sacramento, along with more than 100 clergy.

In 1903, the Little Sisters of the Holy Family, a religious order based in Sherbrooke, Quebec, sent a contingent of nuns to Menlo Park to take care of the domestic services, such as cooking, laundry and cleaning, at St. Patrick's.

Due to increased enrollment, the archdiocese opened St. Joseph's College in 1924 in Mountain View, California.

[7] In 1994, the Little Sisters of the Holy Family left STPSU due to a lack of personnel; they were replaced with nuns from the Oblates of Jesus the Priest from Mexico.

[3] In February 2017, Bishop Patrick Joseph McGrath announced that the Diocese of San Jose would send its seminarians to the University of Saint Mary of the Lake/Mundelein Seminary in Mundelein, Illinois, instead of to STPSU.

The STPSU board of trustees had recently told them that it wanted to establish a more collaborative administration of the institution.

[9] In April 2022, STPSU introduced a preparatory first year of seminary training that it called the Propaedeutic Stage.

[10] All six men who graduated from STPSU in 2023 with both Master of Divinity and Bachelor of Sacred Theology degrees were ordained in their dioceses.