Opened in 1889, O'Connor was the first hospital in Santa Clara County. The original O'Connor Sanitarium, as it was called, was built by Judge Myles P. O'Connor and his wife, Amanda, on 15 acres of country property at the corners of Race and West San Carlos streets.

Known for being benefactors of many charitable organizations, the O'Connors' original intent was to build a home for the elderly, but community needs determined that a hospital was the priority. At the suggestion of Archbishop Riordan of San Francisco, the O'Connors' asked the Daughters of Charity to operate the hospital. On May 1, 1889, four Daughters of Charity members moved into the almost-ready facility, which opened that same month.

In 1953, O'Connor Hospital moved to its present site on Forest Avenue. Still affiliated with the Daughters of Charity Health System, the hospital continues to provide care with a special focus on the needs of the poor and underserved.