Seeing the need for higher education in Clinton County and surrounding areas, the Sisters of St. Francis established Mount St. Clair College in 1918. This liberal arts institution was also a normal education college approved between 1932 and 1954. In 1942, 60% of rural teachers in Clinton County and 62% of the teachers in the Clinton City school system received all training at Mount St. Clair College. In 1950, the North Central College and School Association first recognized Mount St. Clair College. Then, the college began to develop rapidly and acquired a monastery building, a new library, a new gymnasium, a science building and a Durham dormitory building. The university eventually became a co-educational school in 1967.
The campus covers an area of 24 acres (9.7 hectares), about half a mile (800 m) from the Mississippi River and about 1600 miles (1600 m) north of Highway 30. The most famous buildings on the campus are the St. Clair Concert Hall, Mount St. Clair Monastery, Novitiate, College and College. Durham and Regis auditoriums provide housing for campus students.
In the 1979-1980 academic year, the college received approval for its first four-year degree, which is the Bachelor of Business Administration program. In the same year, Mount St. Clair College merged with St. Mary’s High School in Clinton to form the alma mater Dei High School (now known as the Prince of Peace Preparatory School). With the release of the college merger, the school began to provide additional four-year courses. In 1997, the sisters left campus and moved into their new mother's home, The Canticle. In 1998, the Durgin Education Center opened, which included new sports facilities including the Kehl Arena.
In 2003, Mount St. Clair College was renamed Franciscan University. At the same time, the university received approval to open its first master's degree online. In September 2004, the school was renamed the Franciscan University of the Prairie to avoid confusion with the school of the same name.