In 1829, philanthropist and former mayor of Charleston Colonel Thomas Roper bequeathed $30,000 to a group of Charleston physicians, known collectively as the Medical Society of South Carolina (MSSC), to build a hospital to treat all sick and injured people "without regard to complexion, religion, or nation." The Medical Society pooled the Colonel’s gift with other funds, built the original hospital on what is now the corner of Queen and Logan streets, and named it for its primary benefactor. The hospital began admitting patients on a regular basis in 1856 in time for the yellow fever, cholera, typhoid fever, and smallpox epidemics that ravaged the city.

When the Union army captured Charleston in February 1865, Roper Hospital and all its property was seized by the Federal government. Roper was returned to its trustees in January 1867, and in June of that year the Roper Board approved a request by the faculty of the Medical College to hold their teaching clinics for medical students at Roper.

On August 31, 1886, an earthquake followed by several aftershocks destroyed the Roper Hospital building. Work on a new hospital on the corner of Barre and Calhoun streets was completed in February 1906, with the mayor of Charleston at the time reporting that "By arrangement with the Medical Society of South Carolina, a hospital has been built, costing something over $125,000, that is as perfect in its appointments as any in the South."

The facility was expanded in 1946 with the completion of a private pavilion. Fifteen years later, cash and securities willed to Roper Hospital by Mr. Victor Morawetz were combined with other funds and a generous grant from the Ford Foundation to modernize the physical plant adding an additional 38 beds and bringing the total bed count to 277. During the 1980s Roper undertook a multi-million dollar expansion program adding the Kronsberg (South) Tower, the Pettit (North) Tower, and a parking garage.

Under the Medical Society’s leadership, Roper Hospital has continued to serve as an industry leader. Especially noteworthy has been Roper’s growth in the last two decades from a single community hospital into Roper CareAlliance, coastal South Carolina’s first and most comprehensive multi-site healthcare system.