It travels eastward across the northern portion of the state, connecting the cities of Kingman, Ash Fork, Williams, Flagstaff, Winslow, and Holbrook.

The highway has major junctions with U.S. Route 93 (US 93; the main highway connecting Phoenix and Las Vegas, Nevada) in Kingman and again approximately 22 miles (35 km) to the east and I-17 (the freeway linking Phoenix to northern Arizona) in Flagstaff.

With the completion of I-40 in 1984, the entire routing of US 66 had been bypassed by Interstate Highways which led to its decertification a year later in 1985.

I-40 enters Arizona from California at a bridge that crosses the Colorado River at Topock in Mohave County.

US 93 south begins to run concurrently with I-40 east as they both swing eastward through Kingman.

The two later separate at exit 71 as US 93 heads toward the south toward Phoenix while I-40 continues east toward Flagstaff.

Along the way, I-40 passes through the town of Seligman, then, at Ash Fork, it meets SR 89, the former U.S. Route that heads south to Prescott.

Next, it passes through Williams, where it has an interchange with SR 64 (exit 165), which heads north toward Grand Canyon National Park.

[1] With the exception of a stretch between Kingman and Flagstaff, I-40 directly replaced the famed US 66 across northern Arizona.

On October 26, 1984, after the last section of I-40 was completed in Williams, US 66 was removed from the state highway system of Arizona.

The road was a popular route for immigrants during the 1860s and 1870s until the transcontinental railroad was built across northern Arizona in the 1880s.

The railroad rejected the proposed rerouting of their main rail lines, citing that it would result in worse grades than what currently exists, and, in order to reduce those grades, considerable lengthening of the rail line would be required.

[15] The proposal was met with stiff opposition, including all four US senators from California and Arizona sending the Secretary of Commerce letters requesting that the routing through Needles be retained.

[26] This was also the last section of US 66 to be bypassed by the Interstate, which led to it being decertified by the American Association of State Highway and Transportation Officials (AASHTO) the following year.