U.S. Route 501 has its southern terminus in the center of Myrtle Beach, South Carolina and proceeds northwest through Horry County seat Conway, then Marion and Dillon, before exiting into North Carolina at an interchange with Interstate 95 at the famed South of the Border tourist trap. It has freeway interchanges with mainline U.S. Route 17 and South Carolina Highway 31 just outside of Myrtle Beach, and is the site of the west end of another freeway, South Carolina Highway 22, between Conway and Aynor in Horry County.

 

Within South Carolina, US 501 has business routes through Conway and Marion, and from Latta in Dillon County to the North Carolina line, at I-95, it overlaps with U.S. Route 301. Additionally, from Myrtle Beach to Marion it forms roughly the eastern half of a notional extension of Interstate 20 from Florence.