Built to replace its predecessor at Dickinson College in Carlisle, Pennsylvania which was destroyed by fire in 1836, the second South College was completed on January 1, 1838.  It was built to the design of Peter B. Smith, and was constructed at a cost of $5,825. 

At first, the second South College contained a dormitory and classrooms for only the College Grammar School.  In later years, however, the building would serve as a library, museum, and science department for the College as well.  Another floor was added to the building in 1887, and the entire structure was refurnished at a cost of $5,215. 

In 1927, South College was razed to provide space for the Alumni Gymnasium.  A third South College was constructed behind the gymnasium in 1848.