It replaced the Old Charleston Museum that burned down due to unknown causes.

[2] Other museums in the category of oldest in the United States include the Peabody Essex Museum in Salem, Massachusetts and the American Philosophical Society in Philadelphia.

[4] The museum's present building was completed in 1980 at 360 Meeting Street, Charleston, South Carolina.

The museum received the remains of Native Americans into their collection in the late 19th through mid-20th century that had been discovered accidentally or through archaeological expeditions.

The museum is also home to the only known fossil of the extinct Pelagornis sandersi, which is possibly the largest flying bird ever discovered.