South Carolina Highway 421 (SC 421) is a 10.360-mile (16.673 km) state highway in the U.S. state of South Carolina.

SC 421 begins where it splits off from US 1/US 78 (Jefferson Davis Highway) southwest of Clearwater; it immediately connects with US 278/SC 125 (Atomic Road).

Heading northeast, it parallels US 1/US 78 to its south, going through the towns of Clearwater, Burnettown, Langley, Gloverville and Warrenville.

A majority of the highway is four-lanes that travels a total of 10.4 miles (16.7 km).

[2] SC 421 was established by 1952 as a renumbering of US 1/US 78, which was realigned onto new four-lane routing just north of it.