South Carolina Highway 381 (SC 381) is a 22.700-mile (36.532 km) primary state highway in the U.S. state of South Carolina.

It connects the towns in eastern Marlboro County.

SC 381 traverses from Blenheim at SC 38 to the North Carolina state line where it continues as North Carolina Highway 381 into Gibson, North Carolina.

As a two-lane rural highway, it connects the towns of Clio and McColl.

In 1931 or 1932, it was extended north to SC 30 (today U.S. Route 15 (US 15) and US 401) in McColl; and west to the community of Marlboro.