Campbellsville University traces its origins to the founding in 1906 of Russell Creek Academy by the Russell Creek Baptist Association. The Academy gradually developed its offerings and a four-year curriculum, becoming accredited as a college. With an expansion of graduate programs, in 1996 the college gained university status.

The president of the university is Michael V. Carter, Ph.D. The immediate past president is Kenneth W. Winters (born 1934). He is a Republican state senator from District 1 based in Murray in southwestern Kentucky. Before Winters, the president was William Randolph "Randy" Davenport of Campbellsville, who served 1969–1988.

Fuller Harding, an attorney and former state representative from Campbellsville, served on the CU board of trustees for five years. His father, Abel Turner Harding (1881–1966), had been instrumental in raising funds to establish Russell Creek Academy, the forerunner of Campbellsville College.

Forest Shely, a physician in Campbellsville and a 1943 graduate of the former Campbellsville Junior College, served as a trustee of the university for 56 years, from 1954 until his death in 2010.

In 2014, representatives from Campbellsville University met with Kentucky Baptist Convention leaders to report that the CU board of trustees had voted to end its Covenant Agreement with the KBC. CU's Board Chairman Dr. Joseph L. Owens said, "Our actions will allow us to select our own trustees but these decisions in no way change the mission or the character of Campbellsville University. We look forward to discussing the new proposed agreement that will continue CU working with the KBC and its churches in areas of joint mission and ministry in the spirit of the Great Commandment and in following the command of the Great Commission."

In February 2017, the CU field house was damaged in a fire. The university will raze the old structure and rebuild it in the same spot. The new structure is expected to be available in time for the new football season in mid-August.