Henderson State University was founded on November 6, 1889, when  members of the Methodist Episcopal Church, South and Arkadelphia civic leaders held a town meeting at the Church to discuss the founding of a Methodist college for Arkadelphia and south Arkansas.

The University was established on March 24, 1890, and was incorporated as Arkadelphia Methodist College. the school was chartered as a 4 year, coeducational baccalaureate liberal arts college. The University held it's first classes on September 3, 1890, with one hundred and ten students and ten faculty members. The name of the school was changed to Henderson College in 1904 in recognition of Charles Christopher Henderson, a Trustee and well known local businessman. In 1911, the name was changed again to Henderson-Brown College to honor Walter William Brown, also a trustee.

At present Henderson offers degree programs through the Matt Locke Ellis College of Arts and Sciences, the School of Education, the School of Business and the Graduate School. In addition to its own degree program in nursing, the University also provides the academic program for the Baptist School of Nursing. The College operates the only aviation degree program in Arkansas and offers pre-professional studies.