St George's was the first of three commissioners' churches to be built in Sheffield under the Church Building Act 1818 (the other two being St Mary's Church, Bramall Lane and St Phillip's Church, Netherthorpe). The church was designed by Woodhead and Hurst at a cost of £15,181 (equivalent to £1,090,000 in 2015), the whole cost being met by the Church Building Commission. It was built in the Perpendicular style, 122 feet (37 m) long and 67 feet (20 m) wide, and consisted of a flat-ceilinged nave with six bays, a single-bay chancel, and a 140 feet (43 m) high tower. Galleries extended the length of the north and south walls, and there was a two-tiered gallery on the west wall. In all, the church could seat 2,000 people. The foundation stone was laid on 19 July 1821, and the church was consecrated by Archbishop Vernon Harcourt on 29 June 1825.
The church closed in 1981 and was unused for a number of years. It was acquired by the University of Sheffield, and in 1994 it was converted for use as a lecture theatre and student accommodation. Prior to this it had been the last of the Commissioners' churches in Sheffield to retain its original form. It is recorded in the National Heritage List for England as a designated Grade II listed building.
In 2010, a nesting box was placed on the church rooftop, which is now home to a breeding pair of peregrine falcons that can be viewed on live stream webcam.