U.S. Route 421 traverses approximately 328 miles (528 km) across North Carolina; from Fort Fisher, on a peninsula between the Atlantic and Cape Fear River, to the Tennessee state line near the community of Zionville.

Majority of the highway is part of the North Carolina Strategic Highway Corridors system. 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 6 lanes. Finding a road named "Old U.S. Route 421" is not uncommon along the entire route.

US 421 starts at a parking/dock area on the Cape Fear side of the peninsula; within a quarter of a mile, the Fort Fisher Ferry Terminal is located where travelers can ride a ferry to Southport. Immediately after the ferry terminal is the Fort Fisher State Recreation Area, where the first and second battles of Fort Fisher took place.

The highway continues north, going through popular tourist destinations in New Hanover county: Kure Beach, Wilmington Beach, and Carolina Beach. US 421 eventually enters Wilmington along the riverside of the city. At Wooster Street, it goes west, merging with several other highways and funnel through Brunswick county before returning back in northwestern New Hanover county; there it links with I-140 before continuing north towards Clinton.

The road between Wilmington and Dunn is mostly two-lane road through the countryside (with exception to Clinton, where it is a freeway bypassing west of the city). There is one rest area located just north of Delway. Most travelers today use I-40, which parallels US 421 10 miles (16 km) to its east. Thus this section will unlikely to ever be widen like it has throughout the rest of the state.

From Dunn to Lillington, it expands into an expressway, connecting the two cities and Campbell University in Buies Creek. At Lillington, it goes through town before redirecting towards Sanford to its west, via two-lane road.

At Sanford, US 421 currently goes through the town, but eventually it will bypass the city entirely with the Sanford Bypass (majority of which already built, but does not link to US 421). Once the Sanford Bypass is completed, it connect Greensboro to Fayetteville on a four-lane highway that bypasses most cities along its route with US 421 and NC 87.

Just west of the US 1/15/501 freeway, US 421 becomes an expressway; passing effortlessly by towns it once serviced: Goldston, Bear Creek, Siler City, Staley, and Liberty.

Near Pleasant Garden, US 421 transitions from an expressway to a freeway by overlapping with I-85; it also goes west from this point till Sugar Grove. As the modern eight-lane I-85/US 421 overlap loops south of Greensboro, it soon connects with I-73 and switches to overlap it. Another six miles later, it switches again to I-40 and continues on towards Winston-Salem. Near Kernersville, US 421 switches one last time with Business Loop I-40 going into downtown Winston-Salem. The freeway section through Winston-Salem is the oldest in the Triad and will typically have some construction for either road or bridge repair; Luckily, people can bypass the downtown area by staying on I-40 then taking exit 188, where US 421 meets up again.

At either exit 1 (via Business Loop I-40) or exit 188 (via I-40), US 421 separates toward Yadkinville. From Winston-Salem to Wilkesboro, US 421 continues on four-lane freeway, much of which was built between 1992-2002. This section of the highway is mostly farmland, with only Yadkinville as a viable place to stop for food and drink. When the highway nears North Wilkesboro, drivers will be able to see the 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. As US 421 enters Wilkesboro city limits, it downgrades to an expressway with various stores and restaurants along it. Travelers should anticipate higher traffic volumes between US 421 Business junction and NC 16 junction in Wilkesboro.

As it leaves Wilkesboro, US 421 begins a gradual climbs up the Blue Ridge Mountains, till approximately five miles from Deep Gap where it climbs up significantly. Fortunately, compared to US 221 and US 321 that heads towards Boone, US 421 is considered the safest by being the least steep and curvy route. Access to the Blue Ridge Parkway is located at Deep Gap, as US 421 continues on towards Boone.

As US 421 enters Boone, the expressway ends into a construction zone that plans to widen the highway to Hardin Street. Once past Hardin Street, the road narrows through the downtown area. Traffic is typically bumper-to-bumper, so drivers can follow the US 421 Truck route as an alternate to avoid the downtown area. Boone is also unique that sister routes US 221 and US 321 connect at various points in town; however only the Truck Routes of US 221, US 321, and US 421 join together as they overlap with NC 105 going southwest around town. After leaving Boone, US 421 continues on as a two-lane road to the Tennessee state line, heading on to Mountain City.

Cape Fear Historic Byway is an 8-mile (13 km) byway in downtown Wilmington. US 421 only makes-up only a small section of the total byway, near Greenfield Parks and Gardens. The overall byway is noted for its scenic urban areas, colonial-era streets, the U.S.S. North Carolina, and the city parks. Other roads and highways that make-up the byway are: US 74, US 17 Bus., 3rd Street, Water Street, Front Street, Castle Street, 5th Street, and Lake Shore Drive.

U.S. 421 Scenic Byway is an 8-mile (13 km) byway from the Blue Ridge Parkway to the South Fork New River near Boone, all within Watauga County. The route is noted for its panoramic views of Snake Mountain and Elk Knob, as well as the forests, horse/cattle farms, and Fraser Fir Christmas Tree farms.

In Boone, a 1.1-mile (1.8 km) section, known as King Street, is being widen from four to six-lanes with a raised concrete median from US 321 (Hardin Street) to east of NC 194 (Jefferson Road). The project cost $16.2 million and is expected to be completed at the end of 2011.

In Kernersville, the roadway improvements and extension of Macy Grove Road will include the construction of a new interchange with I-40 Business/US 421. Property acquisition is to begin in 2012.

In Winston-Salem, shared with I-40 Business, a 1-mile (1.6 km) section from west of Fourth Street to east of Church Street has begun project development studies to completely upgrade and streamline. The project includes removing the existing pavement and replacing it with new concrete pavement, upgrade and modernize entrance and exit ramps, and replace most of the bridges on and over the freeway. No cost or time frame has been given at this time.

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. Early estimates range from $950–$1.1 billion. The environmental impact study is expected to complete in 2014, a record of decision and a complete financial feasibility will be done in 2015.

Note – Exit numbers west of Winston-Salem are aligned when US 421 went north around Greensboro in late-1980s/early-1990s. As a result from realignments in Greensboro, the actual mileage vs. exit number mileage is off by an average of 3.5 miles (5.6 km).

Though the highway is commonly known as "421" throughout the state, the highway does have other known names it uses locally in areas.