US 123 parallels I-85 to the north as it connects the Northeast Georgia cities of Clarkesville and Toccoa with the western Upstate South Carolina communities of Westminster, Seneca, Clemson, Easley, and Greenville.

[6][7] US 123 and SR 184 gain a center turn lane and cross a Norfolk Southern rail line as they approach the downtown area.

US 123 passes the Toccoa Amtrak station and intersects SR 17 Alternate (Big A Road), where the center turn lane ends.

US 123 passes by the historic site Travelers Rest before crossing the Tugaloo River branch of Lake Hartwell into Oconee County, South Carolina.

Highways reduce to two lanes to pass through downtown Westminster, which includes the historic Southern Railway Passenger Station.

At the east end of downtown, US 123 and US 76 veer onto Main Street, which becomes a four-lane road with center turn lane.

US 123, US 76, and SC 28 head east concurrently along the north side of Seneca south of Lake Keowee.

[6][8] US 123, US 76, and SC 28 cross the railroad and continue east from Seneca as Clemson Boulevard, a four-lane divided highway.

The highways begin to closely parallel the railroad shortly before they meet the western end of SC 93 (Pendleton Road), which provides access to Clemson University.

[6][8] US 123 continues east as a four-lane road with center turn lane to its directional intersection with the eastern end of SC 93 (Greenville Road), where the U.S. Highway becomes a divided highway again and briefly parallels the Greenville District rail line.

U.S. Route 123 Business (US 123 Bus) was established in 1958 as a renumbering of mainline US 123 through downtown Seneca, via North 1st Street.

U.S. Route 123 Business (US 123 Bus) was established in 1958 as a renumbering of mainline US 123 through downtown Easley, via Liberty Drive and Main Street.

It was decommissioned in 1963 when mainline US 123 was rerouted further south along new freeway; the alignment was renumbered as part of SC 93.