The University of St. Francis grew out of an earlier high school and Sisters’ Normal Institute (an institution created to train high school graduates to be teachers) by the Congregation of the Sisters of St. Francis of Mary Immaculate in Joliet established on August 2, 1865 by Mother Alfred Moes.

St. Francis Academy ceased operation in Tower Hall in 1956, and in 1957 the Caritas fundraiser gala began raising money for student scholarships.

By 1980, CSF was granted graduate degree-granting authority and introduced a master's program in health services administration.

The 1990s brought further development, including the Moser Performing Arts Center being added on to Tower Hall.

The university's St. Bonaventure Campus opened in downtown Joliet with additional classrooms, offices, and a business incubator.

In 2018, new construction was completed on the LaVerne & Dorothy Brown Science Hall on the main campus.

[8] The university also offers a Physician Assistant program at a campus site in Albuquerque, New Mexico.

The university is a member of the National Association of Intercollegiate Athletics (NAIA) and is part of the Chicagoland Collegiate Athletic Conference (CCAC)[10] for most of its sports since the 1973–74 academic year; while its football team competes in the Midwest League of the Mid-States Football Association (MSFA).

Four years later, in 1986, a recreation center was built for the athletic department, and a men's football program was introduced.

A major milestone occurred in 1993 when the CSF baseball team won the school's first-ever NAIA World Series national championship under head coach Gordie Gillespie, who became college baseball’s all-time winningest coach.

USF's men's cross country team won the NAIA National Championship in 2012, a year which also marked the renaming of the recreation center to the "Pat Sullivan Center" in honor of long-time basketball coach and athletic director Pat Sullivan.

In 2021, the men's bowling team added to the university’s accomplishments by winning the NAIA Championship.