US 421 starts at a parking/dock area on the Cape Fear side of Pleasure Island. 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. 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, and Carolina Beach. US 421 eventually enters Wilmington along the river side of the city. At Wooster Street, it goes west, overlapping with several other highways and funnels through Brunswick County before returning in northwestern New Hanover County; there it links with Interstate 140 (I-140) before continuing north towards Clinton.
From about three miles (4.8 km) north of the I-140 interchange, the road remains a four-lane divided highway for another ten miles (16 km). After its intersection with NC 210, it becomes a rural two-lane highway for much of its remainder until Dunn. 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). There is one rest area located just north of Delway.[3] US 421 meets I-95 in Dunn. From Wilmington to Dunn, the route parallels I-40 approximately ten miles (16 km) to US 421's east.
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. Upon reaching the junction with US 401, NC 27, and NC 210, all four routes collect onto a thoroughfare heading south over the Cape Fear River into downtown Lillington. US 421 then splits off to the west, following two-lane Front Street until Sanford (though speed limit never actually increases).
Upon reaching Sanford, US 421 formerly followed Horner Boulevard with NC 87 to cross downtown, but it is now rerouted onto the recently completed Sanford Bypass, the entirety of which is freeway. It runs concurrent with NC 87 Bypass until the US 1/US 15/US 501/NC 87 interchange, from which it continues until the end of the bypass near Cumnock.
For the rest of its route until Wilkesboro, US 421 remains almost entirely free-flowing. It is an expressway from Sanford to just south of Siler City, bypassing Goldston, Bear Creek, and Siler City. From here to the Greensboro Urban Loop, US 421 becomes a freeway, bypassing Staley, Liberty, and Julian. All of these cities/places were connected by US 421's old alignment, now called some variant of Old US 421 for the majority of its route.
Near Pleasant Garden, US 421 joins I-85 on the Greensboro Urban Loop, staying with the loop as I-85 leaves and I-73 joins it. Another six miles (9.7 km) later, US 421 leaves the Greensboro Urban Loop to join I-40 and continue westward towards Winston-Salem. Near Kernersville, US 421 joins Salem Parkway which was formerly I-40 Business and even earlier a former alignment of mainline I-40, going through downtown Winston-Salem. Extensive reconstruction of the freeway through Winston-Salem was completed from 2016 to 2020, and when completed I-40 business was removed from it, and the Salem Parkway name became official.
West of Winston-Salem and its final interchange with I-40, US 421 continues as a freeway towards Yadkinville and Wilkesboro. 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.As US 421 enters Wilkesboro city limits, it downgrades to an expressway with various stores and restaurants along it.
As it leaves Wilkesboro, US 421 begins a gradual climb in elevation, until approximately five miles (8.0 km) from Deep Gap, where it climbs up the steep escarpment along the eastern edge of the Blue Ridge Mountains. Access to the Blue Ridge Parkway is located at Deep Gap, as US 421 continues on towards Boone.
As US 421 approaches Boone, the expressway comes to an end just before an intersection with Old US 421. The road continues into Boone as four lane boulevard, becoming two lanes at the intersection with US 321. US 321 north, US 421 north, and NC 194 south all run concurrent through the downtown area via King Street. After leaving Boone, US 421 continues on as a two-lane road to the Tennessee state line, heading on to Mountain City.
