On May 31, 1909 the 37th General Assembly of Arkansas passed Act 378 to create a Tuberculosis Sanatorium, appropriations included $50,000 for construction and $30,000 for maintenance. The Booneville Sanatorium opened in 1910, in Booneville, Logan County, Arkansas with a small building with 64 beds. There was an outbreak of TB across the nation and soon people were brought to the sanatorium. With the rapid increase of TB cases, new buildings were constructed to house the patients. The new main hospital was named the Nyberg Building after Leo E. Nyberg, former patient and state legislator from Phillips County. The Nyberg Building was 528 feet long, 5 stories high, and capacity of 512 beds. The building was finished in 1941 shortly after the death of Nyberg in 1940.

The Booneville Sanatorium was for white patients only with men, women, and children being separated at all times. The sanatorium built specifically for African Americans was the Thomas C. McRae Sanatorium built in October, 1930 in Alexander, Pulaski County, Arkansas.

The Booneville Sanatorium housed up to 5,000 patients at a time in peak years and treated over 70,000 patients through its operation. The complex had around 300 employees seventy-six buildings and approximately 896.18 acres with dormitories their own fire station, post office, store for personal items, chapel, laundry room, water treatment plant, and independent telephones. The Sanatorium discharged their last patients on February 26, 1973 and the Sanatorium turned into a facility for the mentally disabled. The Sanatorium was once one of the largest TB treatment centers of the world. Now the Sanatorium is vacant and remodeled by the Booneville Historic Preservation Society.