The Indiana University academic presence in Indianapolis began in 1891 when Professor Jeremiah Jenks from IU-Bloomington taught an economics course in the city. Other IU faculty members taught courses in other disciplines over the next few years.

In 1912 IU established the Extension Division to oversee classes offered outside of Bloomington. In 1916 the division opened a center in Indianapolis with Ray S. Trent as the officer-in-charge and Mary B. Orvis as his assistant. During World War I Orvis, along with other Extension Division staffers, went to Washington, D. C. to work for the Committee on Public Information. When Ray Trent resigned as the officer-in-charge of the Indianapolis Center in 1918, Robert E. Cavanaugh succeeded him. In 1921 Cavanaugh became the director of the Extension Division, a position he would hold until 1946. Mary Orvis returned to the Center as officer-in-charge with Gertrude Heberlein as her assistant.

Orvis stepped down from her position in 1945 and was succeeded by Roy W. Feik. In 1946 Robert Cavanaugh resigned as the director of the Extension Division. Among the many changes made to the division at that time was the renaming of the division to Division of Adult Education and Public Services, the elevation of the head of the division to the rank of dean, and the change of title of the chief administrators of the extension centers from officer-in-charge to director.

In 1955 Feik resigned from the director's position in order to teach full-time at the Indianapolis Center. Gertrude Heberlein served as acting director for a year, then Virgil Hunt, director of the Kokomo Center, became the director of the Indianapolis Center in 1956. In 1966 Hunt left the position to become the registrar of the IU Medical Center. Assistant Dean Joseph Taylor was acting dean until 1967, when he was named dean. He held the position until a 1972 academic reorganization of IUPUI's undergraduate programs dissolved the Downtown Campus and created the Schools of Liberal Arts, Science, and Engineering and Technology. Taylor became the first dean of the School of Liberal Arts.

During most of its 56 years of existence, the Downtown Campus offered primarily freshman- and sophomore-level classes. A few upper-level classes were available in business; upper-level classes in other disciplines were primarily for teachers working on a graduate degree in education. Classes were held in the afternoons and evenings; morning classes started in the 1960s when demand for classes exceeded what could be accommodated with afternoon and evening classes.

During its first twelve years, the Indianapolis Center occupied several different quarters. From 1916 to 1920, it was in rented space in the Merchants Bank Building at Washington and Meridian Streets. During 1920-1921 it was in the former School of Medicine building at 102 North Senate Avenue. From 1921 to 1928 it rented space at 319 North Pennsylvania Street. In 1928 IU purchased the Bobbs-Merrill Building at 122 East Michigan Street to house the Indianapolis Center and the School of Social Work. In 1948 the university acquired the Indiana Lumbermen's Insurance Company building at 518 North Delaware Street to provide additional space. In 1963 the university began leasing the Carpenters Building at 222 East Michigan Street and in 1967 purchased the Marott Building at 902 North Meridian Street for use as classroom buildings.

Discussions about building new facilities for the Downtown Campus began in the 1950s. Early proposals recommended erecting a new building along Pennsylvania Street, directly west of the existing campus buildings. Later discussions included the options of new buildings near the IU Medical Center or in another part of the city. The final decision was to build near the Medical Center. The Downtown Campus moved into the new buildings on West Michigan Street opened in the spring of 1971, and its former buildings were torn down to make way for the Minton-Capehart Federal Building.