US 421 enters Virginia at State Street, which follows the boundary between Bristol, Virginia, and Bristol, Tennessee, and heads north on Commonwealth Avenue, which also carries
US 11E,
US 19, and
SR 381. Prior to spring 2011, US 421 followed a more convoluted routing on Martin Luther King Jr. Boulevard, Cumberland Street, Piedmont Avenue, and Goode Street (all but MLK also being
U.S. Route 11-19 Truck). US 421, US 11E, US 19, and SR 381 meet the southern end of SR 113 at separate intersections: Cumberland Street carries northbound SR 113 east and Sycamore Street carries the westbound direction. The four highways continue north to east–west Euclid Avenue, where US 11E has its northern terminus. SR 381 continues north along Commonwealth Avenue to the southern end of
Interstate 381 (I-381), a spur south from I-81. US 19 turns east to join
US 11 on eastbound Euclid Avenue. US 421 turns west onto four-lane
divided Euclid Avenue and runs concurrently with
US 11W, which has its terminus at the intersection. The two highways cross Norfolk Southern's
Appalachia Division rail line at grade and pass
Devault Memorial Stadium, home of the
Bristol Pirates. US 11W and US 421 diverge an at intersection with
Tennessee State Route 1 (State Street) at the state line. US 11W continues into Bristol, Tennessee as State Street while US 421 heads northwest on Gate City Highway. 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. US 421 and US 58 exit the city of Bristol and enter
Washington County as a two-lane undivided road. The U.S. Highways head northwest through gaps in Big Ridge, Walker Mountain, then curve southwest through the Rich Valley. At the Washington–
Scott county line, US 421 and US 58 veer northwest again and follow a curvaceous path through Shelly Ridge and Cove Ridge, after which the highways follow Cove Creek southwest through the valley of the
North Fork Holston River until the highways turn northwest, cross the river, and pass through Hilton Gap in Pine Ridge. 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). US 421, US 23, and US 58 run concurrently with the Appalachia Division rail line through
Moccasin Gap, where Moccasin Creek passes through
Clinch Mountain. The U.S. Highways enter the town of Gate City; three
congruent business routes pass through the center of town while the mainline of the U.S. Highways follows the flank of Clinch Mountain to the south of town. US 421, US 23, and US 58 receive their three business routes at an interchange west of Gate City. The U.S. Highways parallel the railroad and Little Moccasin Creek west between Clinch Mountain to the south and Moccasin Ridge to the north. 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. US 421, US 23, and US 58 pass by
Glenita, where the railroad splits north to pass through the Natural Tunnel, the centerpiece of
Natural Tunnel State Park. 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. 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. The U.S. Highways descend the mountain to Wallens Creek, then pass through several sweeping curves before diverging at the hamlet of
Dot. US 421 heads northwest and passes through the hamlet of
Woodway before crossing the
Powell River. The U.S. Highway follows the North Fork of the Powell River to the town of Pennington Gap, where the highway passes under the Appalachia Division rail line intersects
US 58 Alternate (Trail of the Lonesome Pine). US 421 and US 58 Alternate head through the center of town along Morgan Avenue before US 421 heads out of town along the North Fork of the Powell River and the rail line through Pennington Gap, which is a
water gap through Stone Mountain. At Stone Creek north of the gap, US 421 meets the southern end of
SR 352 (St. Charles Road), which serves the town of St. Charles to the north. 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. ==History==