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

US 421 traverses the state from east to west travelling from the coastal plains to Appalachian Mountains.

Despite being signed as north–south, much of the routing of US 421 in North Carolina runs in an east–west direction, particularly between Greensboro and the Tennessee state line.

Portions of US 421 have been upgraded to freeway standards including the majority of its routing between Sanford and North Wilkesboro.

In 1932, the highway was extended northwest through Sugar Grove to Mountain City, Tennessee, and southeast along NC 60 to Wilmington.

[2] Because of this designation, the state has made numerous changes converting a rural two-lane highway into a major freeway/expressway with 4 or more lanes.

Within one-quarter mile (0.40 km), US 421 passes through its unsigned junction with NC 211 and the approach to the Fort Fisher Ferry Terminal, where travelers can board to cross the Cape Fear River toward Southport.

The exception is in Clinton, where it follows Faircloth Freeway to bypass the city, running concurrent to US 701 for about four miles (6.4 km).

[1] After crossing downtown Dunn and Erwin immediately to the west, US 421 becomes a four-lane divided highway again until reaching Lillington, with a short segment in Buies Creek containing a center lane and reduced speed limit as it crosses Campbell University.

US 421 then splits off to the west, following two-lane Front Street until Sanford (though speed limit never actually increases).

Another six miles (9.7 km) later, US 421 leaves the Greensboro Urban Loop to join I-40 and continue westward towards Winston-Salem.

When the highway nears North Wilkesboro, the highway passes North Wilkesboro Speedway (access via exit 282); there is also a visitor center built in 2009 as the state's first environmentally friendly rest area, located at mile marker 283.

After leaving Boone, US 421 continues on as a two-lane road to the Tennessee state line, heading on to Mountain City.

[7] From 1962 to 1963, US 421 was realigned onto a new road near Sugar Grove and Zionville, leaving the communities of Amantha and Mabel.

In Harnett County, US 421 was moved north, avoiding the community of Mamers, and enters Lillington via Front Street.

[7] From 1994 to 1999, US 421 was removed from all surface roads from Kernersville to Greensboro, following I-40 to Joseph M. Hunt Jr Expressway.

US 421 was realigned in Greensboro during 2008 to follow the new southern loop, overlapping with I-73 and I-85 to Joseph M. Hunt Jr Expressway.

[15] The passage of the Infrastructure Investment and Jobs Act in November 2021, proposed to upgrade US 421 to Interstate status, possibly as I-685.

In August 2022, the Piedmont Triad Partnership proposed upgrading the existing US 421 to an interstate from Winston-Salem to Wilkesboro.

[21] The Wilkes County commissioners approved a resolution supporting action that is part of the process of getting US 421 designated an interstate the same month.

[21] In April 2024, a local organization, called Carolina Core, made the recommendation to designate the spur route as I-777.

[23] In New Hanover and Brunswick counties, the Cape Fear Skyway has begun its project development studies (since 2007) to build a toll road and bridge that will bypass Wilmington.

[27] While in August 2019, NCDOT halted design and planning of the bridge, putting the project on hold indefinitely.