Chattanooga Medical College opened in September 1889 under the direction of Dean E. A. Cobleigh. The faculty was comprised of local physicians and a pharmacist. Loosely under the administration of U.S. Grant University, the school operated with a large degree of autonomy. The curriculum of Chattanooga Medical College included anatomy, , and , and the terminal degree offered was an M.D., which could be granted after two years of satisfactory coursework. In 1892, Chattanooga Medical College took an active part in the organization of the Southern Medical College Association. Not long thereafter, it raised its standards for graduation to three years of coursework, and encouraged four years. Unlike the Chattanooga campus of U.S. Grant University, the medical school attracted students from across the United States and even from Canada. Additionally, it maintained a public clinic and a close relationship with nearby Baroness Erlanger Hospital.

Classes were originally taught in a school building leased from the city of Chattanooga, then in a building near the intersection of Georgia Avenue and East Ninth Street. In 1896, the school moved into the vacant west end of Old Main. After years of fundraising efforts, construction on a building for the Medical College began in 1901. This building was the second structure of note to be completed on the university campus, after Old Main. In 1903 the Chattanooga Medical College building, located near the corner of Vine Street and Baldwin Street (just South of present day Brock Hall), was dedicated with great fanfare. Dean E. A. Cobleigh died in 1905 and leadership of the Chattanooga Medical College went to his associate J.R. Rathmell. A number of changes within the Methodist Episcopal Church changed the dynamic of its relationship with the newly renamed University of Chattanooga and the university was granted more authority. As a part of this, Chattanooga Medical College was discontinued in 1910 so that the university's resources could go towards developing accredited undergraduate programs.