The institution opened as Bethel Female High School in Hopkinsville, while the Russellville campus opened as Russellville Male Academy.
The Hopkinsville campus changed its name to Bethel College for Women four years later in 1858, taking in students continuing with the program.
During the Civil War, the Russellville Convention, a meeting to set up a Confederate government of Kentucky in 1861, met at Bethel Female College.
The Hopkinsville campus was used as a hospital during a black measles epidemic from 1861 to 1862.
Later, during World War II, the Hopkinsville campus was closed from 1942 to 1945 and the rooms rented to Camp Campbell army officers.