Founded in 1895, St. James Presbyterian Church began with members from the former Shiloh Presbyterian Church, first gathering at the Odd Fellows Hall on West 32nd Street.

After several relocations, including a move due to the construction of Penn Station, the congregation followed the Great Migration northward, settling in Harlem in 1915. By 1927, they moved into their current home at 141st Street & St. Nicholas Avenue, a building originally designed for Lenox Presbyterian Church. The building was designed by Ludlow & Valentine and completed in 1905.