In South Carolina, US 276 only runs in Greenville County, for a total of 43.3 miles (69.7 km); beginning at the I-385/I-185 junction in Mauldin.

A two-mile portion of US 276 between Greenville and Travelers Rest is an expressway complete with shoulders, exits, a grass median, and a speed limit of 55 miles per hour.

After Marietta, US 276 climbs about 2,000 feet (610 m) to Caesars Head State Park in the Blue Ridge Mountains, 3 miles (4.8 km) from the North Carolina border.

Many trailheads used for hiking, mountain biking, and horseback riding lie along US 276 in this area and roads connecting to it.

Drivers will also find roadside campgrounds, picnic areas, waterfalls, and two museums — the Pisgah Center for Wildlife Education and the Cradle of Forestry in America — along the road or within a short distance of it.

Between 1959-61, US 276's realignment onto new freeway was complete with a connection with I-26 in Clinton, the remainder of its former route to Laurens was replaced by SC 14.