According to The Unitarian: Volume XII, published by Geo. H. Ellis of Boston in 1897, the Unitarian Church in San Francisco was born on Sunday, October 20, 1850, at a meeting held in Simmon's Atheneum Hall on Commercial Street. In November of the same year, Captain Frederick William Macondray became one of the founding trustees of the church.

In 1853, the Unitarians built their first San Francsico Church at 805 Stockton Street near Sacramento Street. When the congregation outgrew this building within a decade, a new church under the ministry of Thomas Starr King was built on Union Square at 133 Geary Street. In 1889, the church moved to its current building, designed by George W. Percy. Today's building remains largely unaltered except for the square turret which replaced a bell tower and steeple destroyed in the Great Earthquake and Fire. The old church on Union Square was replaced by the City of Paris Department Store.

Prominent Unitarians associated with the early days of the church in San Francisco were James Otis, George Shreve, Leland Stanford, Bret Harte, Andrew Hallidie, and Ralph Waldo Emerson. Two later members of the congregation were Julia Ward Howe and Edward Everett Hale.