U.S. Route 221 (US 221) is a part of the United States Numbered Highway System that runs from Perry in northern Florida to Lynchburg in central Virginia. In South Carolina, the highway runs north to south from the Georgia state line near Clarks Hill to the North Carolina state line near Chesnee. While in the state, the highway passes through Greenwood, Laurens, Woodruff, and Spartanburg. The highway mostly travels through rural parts of the Piedmont region of the state.

Established in 1932, US 221 was connected from North Carolina, from north of Cowpens National Battlefield to Greenwood, connecting the cities of Spartanburg, Woodruff, Laurens, and Waterloo. In 1941, US 221 replaced South Carolina Highway 110 (SC 110), going due north from Chesnee to the North Carolina state line; its former route became US 221 Alternate. In 1954, US 221 was extended south to Bradley and McCormick, then south over the Clarks Hill Dam into Georgia; this replaced part of SC 10 and part of SC 670.

Between 1962 and 1964, US 221 bypassed Roebuck. Between 1968 and 1970, US 221 was rerouted onto the Greenwood Bypass and its current routing south of US 25/US 178, replacing the remaining part of SC 670. The old route through Greenwood became SC 72 Business and an extension of SC 10.

There is one alternate route in South Carolina.