The highway was 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 in McColl; and west to the community of Marlboro. In 1934, the westernextension 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.