The founders of the College of Charleston included six Founding Fathers of the United States, including three who signed the Declaration of Independence: Thomas Heyward Jr., Arthur Middleton, and Edward Rutledge; and three who signed the Constitution of the United States: Charles Pinckney, Charles Cotesworth Pinckney, and John Rutledge.

During the Antebellum era, further development efforts in the college resulted in the construction of Randolph Hall and the President's House, both of which were built using slave labor.

During the mid-20th century, several African Americans attempted to apply to the racially segregated college as part of the Double V campaign against racism in the United States, but they were all rejected.

Though the college became a private institution to avoid being racially integrated during the civil rights movement, black students were admitted starting in 1967 as a result of external pressure.

Outside of downtown Charleston, the campus includes the Grice Marine Lab on James Island, the J. Stewart Walker Sailing Center and the Patriots Point Athletic Complex in Mount Pleasant and the 881-acre (357 ha) Stono Preserve.

In the 2020 presidential campaign, the series hosted Joe Biden, Pete Buttigieg, Julian Castro, Tulsi Gabbard, Amy Klobuchar, Beto O'Rourke, and Bernie Sanders.