The Original Normal School Building burned down on April 8, 1902, and was replaced in 1906 by Academic Hall, the school's domed landmark building. It was designed by Jerome Bibb Legg, who also designed the St. Louis Exposition and Music Hall, and includes light fixtures from the 1904 World's Fair.

In the 1950s Southeast Missouri State College had an enrollment of approximately 1,600 students and steadily increased to more than 7,000 students in the 1970s due to low tuition costs, aggressive recruiting, and the construction of Interstate 55 between St. Louis and Cape Girardeau. The College also moved away from its focus on only training teachers and began to offer courses of study in business, nursing, and the liberal arts. Due to this expansion of curriculum and student body population, the college officially became Southeast Missouri State University in 1972. The physical size of the campus also grew in this same period. In 1956, the institution had ten buildings on campus. By 1975, the number had increased to twenty-two buildings. In 1998, the university acquired the former St. Vincent's Seminary on the Mississippi river. This property has been redeveloped as the Earl and Margie Holland School of Visual and Performing Arts, which opened in Fall 2007.