After the "Trail of Tears" the missionaries returned to Chattanooga and began to work among the English, Scots-Irish, and Welsh in the community and helped plant the new church.

From the 1880s until 1910, when its current building was opened, First Presbyterian was located at the southwest corner of Georgia Avenue and Seventh Street.

[2] There have been thirteen pastors of the church including notable clergy such as Thomas McCallie (whose sons founded The McCallie School), Jonathan Bachman (former Confederate chaplain, former Moderator of the Presbyterian Church in the United States, 1910), James Fowle, and Ben Haden.

One of his successors, Ben Haden, who served First Presbyterian from 1967 to 1999, was later to inaugurate the long-running radio ministry "Changed Lives" on WFLI in Chattanooga.

The congregation has a history of support for foreign missions and is active today, through partnerships with other churches and agencies, in numerous parts of the world.