Being one of the longest and most important highways in the state, it connects the cities of Anderson, Columbia, Sumter and Florence.

US 76 enters South Carolina across the Chattooga River, then continues southeast toward Westminster.

From Clemson, the road heads southeast toward Anderson, intersecting Interstate 85 (I-85), then east toward the small towns of Belton and Honea Path.

US 76 provides local access to the communities of Laurens, Clinton, Newberry, Prosperity, Chapin, and the other smaller towns in the area.

It then continues east out of Florence to the small towns of Marion and Mullins, then into North Carolina.