In 1835 Rev. J. F. Cowan, minister of the Apple Creek Presbyterian Church in Pocahontas [MO] organized the First Presbyterian Church in Cape Girardeau. The first congregation consisted of eight members and met on March 1, 1835, at the home of Capt. Ezra Dutch.

Eventually, a lot was purchased on Lorimier Street, and a two story brick building was erected facing Lorimer. The structure was completed in June 1854 The second floor held the sanctuary and the first floor was used for Sunday School and by the Cape Girardeau Academy for Boys. Later, the first floor was used as the first public school in Cape Girardeau was held in that building.

In 1857 the congregation obtained the first full time minister, the Rev. Franklin Patton. He and his successors put the church on a more solid footing, but the Civil War brought on a new crisis. The congregation was split and many people left the community rather than take a loyalty oath to the U.S. Government.

Around the turn of the century, the comer lot, to the north of the two-story church, was purchased. The old church was razed in 1901 and a second church was built on the corner in 1902 and dedicated in March 1903. The education building was built in 1929.

Over a period of years, as the church grew and the sanctuary building became old and expensive to operate, and a new building was constructed, dedicated on November 27, 1966.