US 421 enters Tennessee from North Carolina at Trade. It is the oldest crossroads community in Tennessee and is the easternmost part of the state. The road "as the crow would fly" is a short distance in Volunteer State but traverses through two mountain ranges. After Trade, it ventures into Mountain City through a 40 mph (64 km/h) zone while bypassing the downtown area. After Mountain City, begins the two mountain ranges and in between them is the area of Shady Valley. The two ranges are a popular motorcycle route known as "The Snake". More than 400 curves over an approximately 30-mile (48 km) ride. After the second mountain range, it flattens out after the South Fork Holston River heading towards Bristol. US 421 enters Virginia on the Old Dominion side of Bristol. Major highway junctions between the NC and VA state lines are State Route 67 (SR 67) in Mountain City, SR 91 the new Mountain City bypass, SR-394, and US 11E.
US 421 enters the Bluegrass State running 272.4 miles (438.4 km) from the Pennington Gap area in Virginia into Harlan County.
For the distance between the Virginia state line and closer to Hal Rogers Parkway, it is a major north–south two-lane highway. However, its passing zones are largely limited to a stretch after the Virginia line, through Harlan and along US 119. US 421 then crosses Pine Mountain and enters Leslie County, turning west at Hyden and paralleling the Hal Rogers Parkway. Between Manchester and McKee, US 421 functions as more of a local road with many curves.
The roadway improves as it descends from the Cumberland Plateau into the Bluegrass Region at Big Hill in Madison County near Berea. It joins US 25 at the Blue Grass Army Depot south of Richmond and roughly parallels I-75 towards Lexington. Through Lexington, it is Richmond Road, Main Street and Leestown Road. The segment between Lexington and Frankfort was once designated Kentucky Route 50 (KY 50). US 62 runs briefly with US 421 in this section.
US 421 winds through the southern part of Indiana as it runs from Madison, in the southeastern part of the state, to Indianapolis. North of Greensburg, US 421 intersects and merges with I-74 west, through the Shelbyville area en route to Indianapolis. Originally, US 421 followed Southeastern Avenue into downtown Indianapolis, where it merged with US 40 (Washington Street) to West Street, then turned north, following West Street, Northwestern Avenue (later MLK Street), and Michigan Road up to the northwest side of the city. US 421 went past the Pyramids, an Indianapolis landmark. North of Indianapolis, US 421 continues to the north-northwest, providing a direct highway link between Indianapolis and Michigan City. US 421 ends at its junction with US 20 on the south side of Michigan City. Originally, the highway's end was a few miles north at the junction with US 12 near the shores of Lake Michigan.
US 421 mainly followed the same route between Clinton and Wilmington. However, there are several old alignments from Clinton to the Tennessee state line.
US 421 bypasses Clinton, old alignment uses local streets.
Between Dunn and Sanford, uses an old alignment, fully connected.
Between Goldston and Greensboro, uses several old alignments but not fully connected.
Between Greensboro and Wilkesboro, uses multiple old alignments of different alignments. In *addition, they are no longer connected consistently.
US 421 bypasses Wilkesboro, with a special US Business route.
Between Deep Gap and Boone, uses a new alignment.
Between Vilas and the Tennessee state line, uses an old alignment.
US 421 is projected to be upgraded to a freeway in Indiana from Greensburg to Versailles. US 421 freeway will go near, or pass through Napoleon and Osgood.[citation needed]
US 76 in Wilmington. The highways travel concurrently to Eagle Island.
US 17 / US 74 / US 76 on Eagle Island. US 17/US 421 travels concurrently to west of Wrightsboro. US 74/US 421 travels concurrently to southwest of Hightsville.
US 11 / US 11E / US 11W / US 19 in Bristol. US 11W/US 421 travels concurrently to the Tennessee–Virginia state line on the Bristol, Tennessee–Bristol, Virginia city line.
I-81 / US 58 in Bristol. US 58/US 421 travels concurrently to southeast of Woodway.
I-74 / I-465 / US 31 / US 36 / US 40 in Indianapolis. I-465/US 36/US 40/US 421 travels concurrently through Indianapolis. US 31/US 421 travels concurrently to Carmel.
US 52 in Indianapolis. The highways travel concurrently through Indianapolis.