In 1833, the same year that the Town of Chicago was incorporated, 20 Presbyterians began meeting at Fort Dearborn. They incorporated as the First Presbyterian Church of Chicago in 1835. In 1842, the church split over slavery. Both sides supported abolition, but disagreed on the method and speed of which to bring it about. Members left to form Second Presbyterian Church.

The congregation of Second Church has worshipped in several locations over the course of its history. In 1847, the church commissioned James Renwick, an East Coast architect, to design a new church. This neo-gothic church, known as the Spotted Church due to the natural tar in the limestone used, was completed in 1851. This church was destroyed in the Great Chicago Fire of 1871.

Second Church again commissioned James Renwick to design a new church at its present location. Renwick built a church reminiscent of English Gothic churches of the 15th century. In 1900, a fire destroyed the roof over the sanctuary, and the nave suffered from extensive water and smoke damage.

The congregation hired a member, Howard Van Doren Shaw, to rebuild and restore the nave. He enlisted his friend and fellow church member, Frederick Clay Bartlett, a muralist and artist, to collaborate on the “decorations.” Shaw and Bartlett dramatically transformed the Sanctuary into the English Arts and Crafts style and increased the seating from 900 to 1200. The sanctuary has changed little since then.