The route connects many smaller communities outside major metropolitan areas and is roughly parallel with Interstate 85 (I-85) to the north and I-20 and I-77 to the south and east.

The route shares the longest concurrency in the state with SC 121, from Whitmire to Rock Hill.

Beginning at the Georgia state line on a bridge over Lake Russell (where it is the continuation of SR 72) SC 72 goes through the town of Calhoun Falls and goes through rural areas of Abbeville County before skirting the county seat of Abbeville on a bypass route.

The route serves as the major thoroughfare for traffic between Abbeville and Greenwood, where it bypasses the downtown area to the north.

Once past Chester, the route turns more towards the north as it enters Rock Hill, where it terminates at SC 122 in the downtown area.

In 1951 or 1952, its routing was adjusted west of Greenwood replacing SC 702 and leaving Old Abbeville Highway (S-1-3 and S-24-1).

[10][11][12][13] In 1954, SC 72 was placed on bypass south and east around Chester; its old alignment became a business route.

[13][15] Sometime between 1990 and 1996, SC 72 was placed on a bypass south and east around Clinton; its old alignment became a business route.

[citation needed] South Carolina Highway 72 Business (SC 72 Bus.)

It follows the original path of the SC 72 mainline route that used to traverse through downtown Clinton, via Broad Street and Willard Road.

was established in 1950 as a business spur into downtown Rock Hill, via Saluda Street, from mainline SC 72, which continued east to terminate at US 21/SC 5 (Anderson Road).