From west to east, it passes through California, Arizona, New Mexico, Texas, Oklahoma, Arkansas, Tennessee, and North Carolina.

Major cities served by the interstate include Flagstaff, Arizona; Albuquerque, New Mexico; Amarillo, Texas; Oklahoma City, Oklahoma; Little Rock, Arkansas; Memphis, Nashville, and Knoxville in Tennessee; and Asheville, Winston-Salem, Greensboro, Durham, Raleigh, and Wilmington in North Carolina.

I-40 begins in the Mojave Desert in California, and then proceeds through the Colorado Plateau in Arizona and the southern tip of the Rocky Mountains in New Mexico.

[3] The lowest traffic volumes are found on rural stretches in New Mexico, Texas, and Oklahoma, where the freeway carries fewer than 15,000 vehicles per day.

Some signs show the control city for I-40 westbound to be Los Angeles, where drivers would follow I-15 south from its western terminus in Barstow.

It reaches its highest point in the state of 7,275 feet (2,217 m) at the Continental Divide (Campbell Pass) in western New Mexico between Gallup and Grants.

The route turns south after Conway and enters North Little Rock, which brings high volume interchanges with I-430, I-30/US 65/US 67/US 167, and I-440/Highway 440 (AR 440).

Just east of the Triad City of Greensboro, North Carolina, it merges with I-85, and the two roads split again just west of the Research Triangle area, passing through Durham and Raleigh.

[17] During the colonial and westward expansion eras, a number of Native American trails existed within the vicinity of what is now Interstate 40.

In 1857, an expedition led by Edward Fitzgerald Beale was tasked with establishing a trade route along the 35th parallel north from Fort Smith, Arkansas, to Los Angeles.

[18] In the early 20th century, a number of auto trails were established by private organizations to aid motorists in traveling between major cities.

[20] US 66, which followed the route from its western terminus to Oklahoma City, became arguably the most famous highway in the United States and has been recognized multiple times in popular culture.

[22] An east−west trans-continental freeway to serve the south-central United States was proposed in multiple plans throughout the 1930s and 1940s for what later became the Interstate Highway System.

[23] The general alignment for the highway that became I-40 was included in a plan released on August 2, 1947, by the Public Roads Administration of the now-defunct Federal Works Agency.

The numbering was subsequently approved by the American Association of State Highway Officials (AASHO) on August 14, 1957, along with most of the system.

[26] From 1963 to 1966, the US government considered a plan, part of Project Plowshare, to use atomic bombs to excavate a path for I-40 through California.

The first stretch in Tennessee reused a short freeway in Knoxville called the Magnolia Avenue Expressway, which was opened in two segments in 1952 and 1955.

[42] After Secretary of Transportation John Volpe authorized the state to solicit bids for the construction of the interstate through the park in 1969, the organization filed a lawsuit, which culminated in the landmark Supreme Court ruling of Citizens to Preserve Overton Park v. Volpe in 1971, which ruled that the state highway department had not adequately explored alternative routes for the interstate.

[43] This case is considered to have established the modern process of judicial review of infrastructural projects, and eventually resulted in the state rerouting the alignment of I-40 through the park onto a section of I-240 in 1981.

The "Big I" interchange in Albuquerque between I-40 and I-25 was reconstructed between 2000 and 2002 in a project that eliminated left-hand entrance ramps and added lanes.

This project was given an honorable mention by the United States Department of Transportation and the FHWA for excellence in urban highway design in 2002.

[51][52][53][54] A $203.7 million two-phase project dubbed "SmartFix 40" resulted in a complete closure of a short stretch of I-40 through Knoxville between May 1, 2008, and June 12, 2009.

[60] On December 23, 1988, a tanker truck hauling liquefied propane overturned on a ramp in the interchange between I-40 and I-240 in the Midtown neighborhood of Memphis, rupturing a small hole in the front of the tank.

[61][62] The leaking gas ignited in a massive fireball, and the tank was propelled 125 yards (114 m) from the crash site into a nearby duplex apartment.

On May 11, 2021, the Hernando de Soto Bridge carrying I-40 over the Mississippi River was closed when inspectors discovered a crack on a tie girder.

[71] The highway was badly damaged during Hurricane Helene in September 2024, with the road closed in multiple locations across western North Carolina due to landslides.

[72] The worst damage was seen near North Carolina's border with Tennessee, where a large portion of the highway was washed into the Pigeon River following a mudslide, resulting in it being indefinitely closed in both directions.