[5] Serving grades 9–12, Mission is the oldest high school on its original site in San Francisco;[6] it has been on 18th Street, between Dolores and Church, since 1896.

The original campus burned in 1922, and the replacement was completed in two stages, the west wing in 1925 and the main building was dedicated by San Francisco mayor James Rolph on June 12, 1927.

That year, the Board of Education purchased a parcel of land from the Jewish Cemetery Association to construct a permanent school building.

The building withstood the 1906 earthquake, and became a neighborhood shelter, while Dolores Park, which stands across the street from the school, became a tent city for displaced residents.

In 1936, California artist Edith Anne Hamlin was commissioned under the Works Progress Administration's Federal Art Project to create a series of western-themed murals for the school.

Two murals showing the founding of nearby Mission Dolores still survive, while the third was lost during a 1970s seismic retrofit.

The building continues to function as a public high school and remains an architectural landmark in the Dolores Park area of San Francisco.