Established in 1937 as a renumbering of SC 12, it originally ran from US 521 to the North Carolina state line in Hancock. By 1964, SC 75 was extended to its current western terminus at SC 5 in Van Wyck, replacing part of SC 504.
South Carolina Highway 75 Truck is a truck route of SC 75 bypassing Van Wyck. It begins at SC 75's southern terminus at SC 5. It follows SC 5 until it has an interchange with U.S. Route 521. It then follows US 521 until they meet SC 75.