In North Carolina, the original highway was to run from the Tennessee state line to Greensboro where the freeway would end at I-85.

[5] All of I-40 is listed in the National Highway System, a network of roads important to the country's economy, defense, and mobility.

Immediately afterward is Waterville Lake, where there are a few at-grade intersections in this location, used as service access for Walters Dam and the Harmon Den Wildlife Management Area.

Shortly after it leaves Asheville, I-40 encounters a steep grade, Old Fort Mountain, with winding roads that pose a hazard to truck traffic.

[17] Continuing through the southern areas of the Winston-Salem, I-40 bears a more eastern direction, passing Hanes Mall and the surrounding commercial developments.

[23] From here, I-40 heads through southwestern Greensboro passing several interchanges that connects to various major areas in the city, including a junction with US 70 which carries Wendover Avenue.

Both the beginning and ending interchanges of this corridor are quite unusual in design and are often operating at above full capacity, leading to frequent traffic jams and incidents.

[31] I-40 continues southeast through rural Johnston County farmland, meeting NC 96 (exit 334) north of Peacocks Crossroads.

[33] I-40 begins to run parallel to the Northeast Cape Fear River and enters Pender County after crossing Rockfish Creek near Wallace.

Continuing south, I-40 once again meets NC 210 at exit 408 near Rocky Point and then crosses the Northeast Cape Fear River into New Hanover County where it picks up the name "Michael Jordan Freeway".

[46] In Duplin County, a section of I-40 6.95 miles (11.18 km) north of NC 24 west of Warsaw to 6.95 miles (11.18 km) south of NC 24 is known as the Henry L. Stevens Jr. Highway, who was a commander of the American Legion and a North Carolina Superior Court judge.

[47] From the Pender–New Hanover county line to the eastern terminus of I-40, the freeway is known as the Michael Jordan Highway, named after the famous basketball player who grew up in Wilmington and was a graduate of the University of North Carolina at Chapel Hill.

[48][49] I-40 has also been given the name Tobacco Road by college sports fans because the freeway links up the four North Carolina schools in the Atlantic Coast Conference.

[51][52] Authorized by the Federal-Aid Highway Act of 1956, North Carolina was originally allocated 714 miles (1,149 km) for their share of the Interstate Highway System; 219 miles (352 km) of which was subsequently allocated for a route from the Tennessee state line, through Asheville and Winston-Salem, to Greensboro.

In both cases, these first freeways were constructed a couple of years prior for US 158 and US 421, respectively, and did not benefit from the 1956 act; as a result, in 1988, the state was able to convince the Federal Highway Administration (FHWA) to build the Winston-Salem Bypass.

[67][68] In November of same year, the North Carolina State Highway Commission (NCSHC) submitted a request to the Bureau of Public Roads (BPR) to extend I-40 east of Greensboro to Raleigh via RTP.

[2][75][76] In 1972, I-40 extended east from US 25 in Asheville to Porters Cove Road (SR 2838) in Oteen; the extension bypassed both US 25A and US 74, where interchanges were built in 1999 and 1973, respectively.

[78] In 1974, a gap was completed between US 276 in Cove Creek to the freeway connector (future Great Smoky Mountains Expressway) near Clyde.

In the end, the routing approval to Wilmington came with a caveat to build new freeway in parallel to US 117 instead of a full upgrade of US 421 as several in the region supported.

The East-West Expressway which carried I-40 through central Winston-Salem, had stretches that both was built to 1950s Interstate Highway standards and predating the system entirely, leading to notable congestion when all combined.

After a study with the city and state, decisions to build a new stretch was concluded, rather than widening and modernizing the freeway through the area, the state lobbied the Federal Highway Administration (FHWA) to allow them new roadway, arguing that since some this section predated the 1956 Act, it never received federal highway dollars for its development and construction, thus I-40 was technically incomplete in Winston-Salem.

In October 1988, the group were able to convince the FHWA, and Governor James G. Martin announced federal approval of $114.1 million for I-40 to be relocated onto the new bypass.

[110] In March 2005, construction crews returned for eight weeks to replace asphalt used in the widening project, which began to deteriorate not long after the lanes opened to the public.

In 2001 and 2003, two state troopers were killed in two separate accidents by speeding trucks that drifted off the road and hit their police car conducting a traffic stop.

This led the North Carolina State Highway Patrol to crack down on speeding tractor trailers and speeders in general through the area.

[120][121][122][123][124] In February 2008, I-40 was relocated onto the southern section Greensboro Urban Loop, marking the first change to I-40 since it was rerouted onto the Winston-Salem Bypass in 1992.

On September 12, 2008, seven months after the initial switch and in agreement with Greensboro DOT and the FHWA, I-40 was rerouted to its original route through the city, I-40 Bus.

[132] In Statesville, the I-40/I-77 interchange (exit 152), originally built as a cloverleaf in the late 1960s, was upgraded to increase capacity and improve safety.

[139] Damage from Hurricane Helene in 2024 washed away the eastbound lanes in the Pigeon River Gorge in several places resulting in a complete closure.

[140] While crews worked to stabilize what was left, plans were made to put all traffic on the westbound lanes by the start of 2025, but further damage has delayed this action.