The football team competes in the Football Championship Subdivision of Division I. SEMO’s Board of Governors announced on February 13, 2025 that Dr. Brad Hodson, Executive Vice-President at Missouri Southern State University, has been named President Designate and will begin duties on July 1, 2025, after Dr. Carlos Vargas’ term ends.

The university has had five names in its history:[6] The Normal building was described in 1883 by Mark Twain in Life on the Mississippi as "a bright new edifice, picturesquely and peculiarly towered and pinnacled—a sort of gigantic casters, with the cruets all complete.

The college moved away from its focus on training teachers and began to offer courses of study in business, nursing, and the liberal arts.

[citation needed] In 1998, the university acquired the former St. Vincent's Seminary located in downtown Cape Girardeau on the Mississippi River.

[9] This property has been redeveloped as the River Campus, which opened in Fall 2007 and houses the Earl and Margie Holland School of Visual and Performing Arts.

[10] The construction of the River Campus began to shift the institution's focus towards the visual and performing arts, which today forms the basis of the university's statewide reputation.

These buildings contain the Donald C. Bedell Performance Hall, the Rosemary Berkel and Harry L. Crisp II Museum, the John and Betty Glenn Convocation Center, the Wendy Kurka Rust Flexible Theatre, the Robert F. and Gertrude L. Shuck Music Recital Hall, and the River Campus Art Gallery.

The Rosemary Berkel and Harry L. Crisp II Museum and Art Gallery features rotating touring exhibitions.

In spring 2005, Southeast eliminated Three Rivers courses from those centers, citing failure of the community college to pay approximately $10,000 in facilities-use fees.

[14][15] The lawsuit was subsequently dropped, and Southeast and Three Rivers recently announced plans to develop a joint bachelor's degree program in social work.