U.S. Route 1 traverses the state of South Carolina completely from southwest to north, passing through such cities as Columbia and Aiken. For much of its length through Richland County, US 1 is called Two Notch Road. The road merges with South Carolina Highway 34 for a few miles around Camden until they split off again and US 1 is called Jefferson Davis Highway after Civil War Confederate leader Jefferson Davis. South Carolina Highway 145 stems from US 1 around the town of McBee. US 52 merges with US 1 and then separates from it again just before the South Carolina—North Carolina border.

US 1 enters South Carolina in North Augusta. From North Augusta to Aiken, US 1 is a divided four lane highway. It goes through the historic district of Aiken, heading north through Batesburg-Leesville, Lexington, into Columbia up to Camden. US 1 parallels Interstate 20, crossing it several times until it branches northeast at Camden. It also has junctions with Interstate 26 and Interstate 77 in Columbia. From Camden, it continues northeast as a two-lane road to the town of Cheraw and Cheraw State Park before entering the state of North Carolina. In Richland County, US 1 is known as Two Notch since the road used to be marked by posts into which two notches were carved. In downtown Columbia, US 1 is known as Gervais Street and passes directly in front of the State Capitol building. South Carolina Highway 421 in Aiken County was formerly US 1 until the expressway was built in the early 1950s. There are several Jefferson Davis Memorial Highway stone markers along US 1 in South Carolina.