Historically, it once connected to US 21 in Pineville, North Carolina, but various changes have left it terminating a few miles short of the current US 21.

US 521 traverses 3.8 miles (6.1 km) from the South Carolina state line to I-485.

Between 1962 and 1964, US 521 was rerouted at the Sumter-Kershaw county line to Camden; the old alignment became an extension of SC 261.

In 1969, US 521 was extended 19 miles (31 km) north, via South Boulevard, and Wilkinson Blvd, then in 1981, by way of Woodlawn Road, and Billy Graham Parkway, to I-85 in Charlotte.

In 2003, the American Association of State Highway and Transportation Officials (AASHTO) approved US 521 to be truncated at its current northern terminus at the Johnston Road/I-485 interchange; its old alignment north to I-85 was downgraded to secondary roads.