Four Presbyterian missionaries (Cyrus Kingsbury, Thomas Archibald, Hilary Patrick, and David Wright) organized the First Presbyterian Church (FPC) of Columbus, Mississippi, in May, 1829. From 1829 until 1834, missionaries from the Mayhew Mission served the church.
In 1844, a brick sanctuary was erected at the intersection of Main Street and Seventh Street North and a charter was obtained. FPC's first pastor was David Wright. In 1864, when the Presbyterian Church in the United States (PCUS) was founded, First Church joined the denomination. Over the course of the next century, FPC's service included the founding of Palmer Home for Children and the establishment of St. Andrew's Presbyterian Church.
The PCUS has split and parts have reunited several times. One split occurred following the Civil War. The result was the formation of two branches: the Presbyterian Church in the U.S. (PCUS), the "southern branch," and the United Presbyterian Church in the U.S.A. (UPCUSA), the "northern branch."
1974 witnessed another split in the church, and several members of FPC voted to join the newly formed Presbyterian Church in America (PCA). The remaining members retained one-third of the church's property, which consisted of the Westminister Fellowship House (formerly used to minister to Presbyterian students at Mississippi University for Women) and a five-acre tract of land from the Leigh Estate. The present sanctuary and fellowship hall were added at the current location, on Bluecutt Road, in 1977.
The PCUS and the UPCUSA reunited in 1983 and became the Presbyterian Church (U.S.A.), of which First Presbyterian-Columbus is a part. The First Presbyterian Church-Columbus is a member of the Presbytery of St. Andrew, the Synod of Living Waters, and the General Assembly of the Presbyterian Church (USA).