The hospital started out as a boarding school for Indians in the late 1800s. The building remained empty for many years until the outbreak of the "white plague" (tuberculosis.) The building was converted into a massive hospital called the Sioux Sanitarium for the TB patients. After the patenting of streptomycin, almost all of the sanitariums in the United States were closed down in the 1940s through the 60s. The building remained empty for several years until it was converted into a public hospital and named the Sioux San Hospital.