South Carolina Highway 381 (SC 381) is a primary state highway in the U.S. state of South Carolina. It connects the towns in eastern Marlboro County.

SC 381 traverses 22.5 miles (36.2 km), from Blenheim, to the North Carolina state line. As a two-lane rural highway, it connects the towns of Clio and McColl.

Established in 1930 as a new primary route, from SC 38, in Blenheim, to SC 9, in Clio. In 1931 or 1932, it was extended north to SC 30 (today US 15/US 401), in McColl; and west to the community of Marlboro. In 1934, the western extension was dropped; while it extended north again to the North Carolina state line. In 1940, SC 381 was extended west again to SC 382, in Scott, only to be truncated back in Blenheim by 1948.

The entire route is in Marlboro County.