It serves the cities of Barnwell and Walterboro while also providing a direct route to Charleston, via US 17.

Starting in Aiken and Barnwell counties, where the Savannah River Site was established, roughly 23 miles (37 km) of highway was removed in what is now restricted area.

A section of SC 64 remained northwest of the Savannah River Site to Beech Island.

[6][7] By 1955, SC 64 was widened to a divided four-lane highway from the Savannah River Site to Barnwell.

[citation needed] South Carolina Highway 64 Alternate (SC 64 Alt.)

South Carolina Highway 64Y (SC 64Y) was a spur route that existed entirely within the northeastern part of Colleton County.

By 1940, it was established from an intersection with SC 64 (now US 17 Alternate) in Round O to a point north of the community.