Designed by Edward C. Jones in 1850, Camden Depot was one of many depots built by the South Carolina Rail Road Company. It served as the terminus on the Charleston-to-Camden line. In 1899 the entire line, including Camden Depot, was bought by Southern Railway. The old wooden structure was replaced by the current brick and metal structure in 1910.
The Department of the Interior documented the depot ion the National Register in 1963. They described it as neglected, with windows broken and overall clutter throughout. From 1977 to 1979, photographer Charles N. Bayless photographed the Charleston area, and the photos taken of Camden Depot note neglect and lack of care for the site.
In 2003, the Children’s Museum of the Lowcountry opened in one side of the Camden Depot. The Children’s Museum is a place where children aged 1-10 can both learn and play at the same time. Additionally, in 2013 a replica of the Best Friend of Charleston, an early commuter train, is on display in the other side of the Camden Depot.