Main Street heads north into the downtown area as US 25 Business; the road also continues south as NC 225 (Greenville Highway).

US 176 reduces to two lanes and continues along a curvaceous path through the Blue Ridge Mountains, crossing the Green River.

[6][7] At the opening of the North Pacolet River valley, US 176 follows Trade Street through the town of Tryon, where the highway meets the western end of NC 108 (Lynn Road).

[6][7] Southeast of Tryon, the U.S. Highway enters South Carolina, where it clips the northeastern corner of Greenville County.

US 176 passes through the hamlet of Gramling before passing through the town of Inman, where the highway expands to four lanes with intermittent center turn lane and intersects SC 292, which heads north as Main Street and south as Lyman Road.

The frontage roads connect with California Avenue, which is accessed from the other direction by a half-diamond interchange after that street's overpass.

US 176 and SC 9 pass the campus of Wofford College, including Gibbs Stadium and Benjamin Johnson Arena, and the headquarters of the Southern Conference, of which Wofford is a part, and crosses Norfolk Southern Railway's Charlotte District.

Southeast of the railroad, US 176 and SC 9 meet the eastern end of SC 296 (Daniel Morgan Avenue), pass along the west side of Converse College, and intersect US 29 (St. John Street) on the east side of downtown Spartanburg.

[6][8] US 176 continues south as a two-lane road, enters Sumter National Forest, and crosses the Tyger River.

The highway meets the western end of SC 213 (Parr Road) west of the town of Peak before entering Richland County.

The highways expand to a four-lane road with center turn lane and diverge at their partial cloverleaf interchange with I-26 (James F. Byrnes Expressway), at which US 76 joins the Interstate to head into Columbia.

US 176 drops to two lanes and continues southeast into the town of St. Andrews, where the highway has an oblique junction with SC 60 (Lake Murray Boulevard) just west of Harbison State Forest.

US 176 crosses over a CSX rail line before reaching an oblique intersection with Main Street, where the highway begins a lengthy concurrency with US 21 and US 321.

The highways follow four-lane Main Street to the Elmwood Park Historic District, where the highways gain a fourth route, US 76, when they turn west onto six-lane divided Elmwood Avenue at the northern edge of downtown Columbia.

Highways follow four-lane divided Blossom Street west across the Congaree River out of the city of Columbia into Lexington County.

Highways pass under a rail line and have an oblique junction with SC 302 (Edmund Road) before re-entering Cayce.

Just south of that interchange, US 176, US 21, and US 321 meet ramps from the southern terminus of I-77 (Veterans Memorial Freeway) opposite Fish Hatchery Road.

Highways reduce to four lanes and cross over CSX's Columbia Subdivision east of the town of Pine Ridge.

US 321 continues south toward Gaston and Swansea while US 176 and US 21 head southeast along Charleston Highway, which drops to two lanes.

[6][8] Shortly after entering Orangeburg County, US 176 intersects US 301 (Five Chop Road) just west of the latter highway's junction with SC 47.

In the center of town, US 176 has a pair of intersections with SC 453, Eutaw Road and Gardner Boulevard, on either side of a grade crossing of CSX's Charleston Subdivision.

US 176 heads southeast through a mixture of swamp and forest with occasional farmland before entering the suburban area around Charleston at its junction with US 17 Alternate (Live Oak Drive) on the edge of the city of Goose Creek.

US 176 expands to six lanes shortly before reaching its eastern terminus at an oblique intersection with US 52 (Goose Creek Boulevard).

There is no direct access from eastbound US 176 to northbound US 52; that movement is made via Thomason Boulevard a few blocks to the northwest.

[20] It was created when US 176 was rerouted onto new alignment north of Union, with the elimination of US 176 Business and extension of SC 18; Connector Road was originally part of Duncan Bypass, built around 1956.