On April 3, 1839, 11 Baptists met in the home of Spencer Hall to organize a Baptist church. The next day, the group met to sign the articles of faith. On Sunday, April 7, the group was organized as a regular Baptist church and baptized its first new member, Mary Mosby. L.H. Milliken was the first pastor. In 1845, Geraldus Buntyn gave the church a lot at the corner of Second and Adams, where a building was constructed and opened in 1847. In 1849, Pastor P.S. Gayle left the church and organized Beale Street Baptist Church. During the Civil War, First Baptist was used as a hospital by the Union Army.
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In 1865, after the Beale Street Church building burned, its members and 49 members of First Baptist organized Central Baptist Church. First Baptist lost many members to yellow fever in 1878 and 1879. The building at Second and Adams was remodeled during 1886-1888, and was subsequently sold in 1905 as the new site for the Shelby County Courthouse. The church moved to Linden and Lauderdale in 1907. In 1924 the church began Radio Station WGBC - believed to be one of the earliest church-owned radio stations. In 1951, the church moved to its present site at the corner of Poplar and East Parkway.