The University of Southern Indiana began in 1965 as a regional branch of Indiana State University, which is located in Terre Haute. Classes were originally held in a former elementary school on the west side of Evansville known as Centennial School – denoting the year it was built in 1876. The property was leased from Bristol-Myers Squibb, which still has a large facility nearby.
In 1971, the school moved to its current campus in western Vanderburgh County. The first buildings constructed were the Science Center and the Wright Administration Building. Slowly the school built facilities, as funding became available during the Indiana State University-Evansville period.