U.S. Route 421 (US 421) is a part of the U.S. Highway System that runs from Fort Fisher, North Carolina to Michigan City, Indiana.

The two highways cross Norfolk Southern's Appalachia Division rail line at grade and pass Devault Memorial Stadium, home of the Bristol Pirates.

The U.S. Highway passes the Bristol Mall before meeting I-81 at a partial cloverleaf interchange, where US 58 exits I-81 and joins US 421 in a concurrency.

Highways head northwest through gaps in Big Ridge, Walker Mountain, then curve southwest through the Rich Valley.

The highways pass through the village of Hiltons and parallel the Appalachia Division rail line southwest through the Poor Valley to the town of Weber City, where the highways meet the northern end of SR 224 (Wadlow Gap Road), cross Moccasin Creek, and intersect US 23 (Main Street).

The highways curve north and parallel the Clinch River to Clinchport, where the road meets the southern end of SR 65 and begins to follow Stock Creek.

After passing through the Devil's Racepath, US 58 and US 421 split west from US 23 (Orby Cantrell Highway) as Daniel Boone Trail just south of the town of Duffield.

[1][2] US 421 and US 58 head west as a two-lane undivided road that crosses the North Fork of the Clinch River and ascends Powell Mountain, on top of which the highways enter Lee County.

Highways descend the mountain to Wallens Creek, then pass through several sweeping curves before diverging at the hamlet of Dot.

The U.S. Highway heads west, following Stone Creek to its source near the Kentucky state line, which coincides with the Tennessee Valley Divide, from which US 421 continues northwest toward Harlan.

It was soon extended southeast along former SR 10 from Pennington Gap to Dot, when U.S. Route 58 was removed from it in favor of a shorter alignment.

By 1951,[8] US 421 had re-entered Virginia, this time splitting from US 58 at Dot to cross into Kentucky, causing State Route 66 to be truncated at Clinchport.