[3] US 178 begins at an intersection with US 64 just west of the town of Rosman within Pisgah National Forest in southern Transylvania County, North Carolina.

The two-lane road, which is named Pickens Highway, heads east into the town parallel to the French Broad River.

The highway veers away from the mainstem of the French Broad to follow its Middle Fork south then east, then turns south and climbs to the Eastern Continental Divide at Eastatoe Gap between Burnt Mountain and Indian Camp Mountain.

[4][5] US 178 enters Pickens County, South Carolina, and its name changes to Moorefield Memorial Highway shortly after it begins its curvaceous and steep descent along Eastatoe Creek to Rocky Bottom.

US 178 curves south at its intersection with SC 288 (Table Rock Road), has a short climb to Mosley Gap between Mosley Mountain and Walnut Cove Mountain, and follows several different creeks through the foothills, which the highway exits as it enters the town of Pickens.

The highway crosses the Six and Twenty Creek arm of Lake Hartwell and temporarily expands to four lanes around its intersection with US 176 Connector, which feeds into SC 28's western bypass of Anderson, Pearman Dairy Road.

US 178 gradually approaches US 76 and SC 28 Business (Clemson Boulevard) as it enters a commercial area before meeting and joining those highways at an oblique intersection.

US 178 and US 76 enter downtown Anderson along four-lane Murray Avenue, which runs one block to the west of Main Street.

NCDOT plans to modernize a 5.85-mile (9.41 km) section of US 178, between Rosman and the South Carolina state line.