The First Presbyterian Church has occupied a site in the middle of Athens, Ohio since 1809. It was founded by Ohio University's first president, a Presbyterian minister, the Rev. Jacob Lindley. Dr. Lindley served this congregation as Moderator and Pastor until 1824. Over the years, thirteen pastors of the church have been either university presidents or members of the faculty. Dr. William Holmes McGuffy, author of the McGuffy's Readers, was called to serve as President of Ohio University and pastor of the church in 1839.

The current church building was dedicated at the Sunday worship service on Feb. 1, 1903.
The old organ was replaced with the largest pipe organ in southeastern Ohio built by the M.O. Moeller Company of Hagerstown, Maryland.

A renovation of the facility took place, and the current 26 rank Holtkamp pipe organ was installed, in 1985. The downstairs was completely rebuilt and modernized. In the sanctuary, the choir area was enlarged and the chancel divided.