In North Charleston, it is concurrent with US 78 for 11 miles (18 km), splitting near Goose Creek.

[7] From Moncks Corner, US 52 is briefly concurrent with US 17 Alt as it enters the Francis Marion National Forest and crosses the Dennis C. Bishop Bridge over the Tail Race Canal of the Cooper River just below Lake Moultrie.

The route traverses the Francis Marion National Forest as it continues northward to St. Stephen.

Though the majority of its routing and signage is north-south, some sections will also be signed east-west at various parts of the state.

In 1939, US 52 was rerouted into a concurrency with US 78 in North Charleston, leaving a section of Meeting Street.