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The hospital was originally the site of the Chattahoochee Arsenal (also known as the Mt. Vernon Arsenal) built in the 1830s. In 1868, under Governor Harrison Reed, the U.S. arsenal property at Chattahoochee became Florida's first penitentiary. The hospital's current Administration Building is the original Officers Quarters of that Arsenal and was added to the National Register of Historic Places in 1973. It had served as a supply depot during the Seminole Wars. The Florida State Hospital was created in 1877 as the Florida Asylum for the Indigent Insane (Ch. 3035, Laws of Florida, 1877). In 1886, it was renamed the Florida Hospital for the Insane. In 1919, it received its present name, the Florida State Hospital. The Board of Commissioners of State Institutions (Ch. 3578, Acts, 1885) had general supervision over the state psychiatric hospital until 1969. At that time, it was placed under the supervision of the Dept. of Health and Rehabilitative Services (Ch. 69-106, Laws of Florida) and later under the Department of Children and Families (Chapter 96-403, Laws of Florida).

Later designated the William DeWitt Rogers Administration Building in 2007.