South Carolina Highway 72 (SC 72) is a 125-mile (201 km) state highway, traversing interior portions of the South Carolina Piedmont region. The route connects many smaller communities outside major metropolitan areas and is roughly parallel with Interstate 85 to the north and interstates 20 and 77 to the south and east. The route is co-signed with S.C. Highway 121 for 49 miles between Whitmire and Rock Hill.

The route travels across the state in a southwest to northeast direction, and is sometimes referenced as an unofficial border between the Midlands and the Upstate regions. Beginning at the Georgia state line on a bridge over Lake Russell (where it is the continuation of Georgia State Route 72) SC 72 goes through the town of Calhoun Falls and goes through rural areas of Abbeville County before skirting the county seat of Abbeville on a bypass route. The route serves as the major thoroughfare for traffic between Abbeville and Greenwood, where it bypasses the downtown area to the north.

Leaving Greenwood, the route heads towards Clinton where it intersects with Interstate 26. Passing the interstate, the route enters into the Sumter National Forest and passes through the small town of Whitmire. From Whitmire until just shy of its eastern terminus, SC 72 is cosigned with SC 121. The route exits the Sumter National Forest and bypasses Chester to the south. Once past Chester, the route turns more towards the north as it enters Rock Hill, where it terminates into U.S. Highway 21 Business in the downtown area.