U.S. Route 301 (US 301) is a 189.704-mile (305.299 km) U.S. Highway that travels north–south from the Savannah River southwest of Allendale to Hamer approaching the South of the Border roadside attraction complex.

US 301 enters South Carolina over the Savannah River southwest of Allendale.

Additional concurrencies include US 321 in and around Ulmer, US 601 between Bamberg and Orangeburg, then US 15 and shortly afterwards Interstate 95 (I-95) in Santee, at exit 97 before all three move across Lake Marion.

Other concurrencies include US 521 from Manning to Alcolu, US 378 in Turbeville, US 52 between Effingham and just south of Florence, US 76 eastbound from east of Florence until Pee Dee, and finally joins US 501 in Latta, where they both approach the South of the Border roadside attraction complex at the interchange with I-95 on the North–South Carolina border.

[citation needed] When I-95 was built across Lake Marion in 1968,[8] US 301 and 15 traveled parallel to it until they were relocated in a triple concurrency in 1987.