The Interstate briefly runs in an east direction through the town of Wildorado before turning back to the southeast.

I-40 runs through eastern Amarillo, passing by the American Quarter Horse Hall of Fame and The Big Texan Steak Ranch.

Development along the route begins to lessen after South Eastern Street as the highway passes near Rick Husband Amarillo International Airport.

The highway runs primarily through rural farmland after leaving the city and enters the town of Groom, passing near a 19-story cross and a leaning water tower.

After the overlap with SH 70 ends, the terrain along the Interstate begins to change from flat plains to a rolling canyon ridge with an observation point near Alanreed.

Bypassed towns included Glenrio, Adrian, Vega, Conway, Groom, Jericho, Alanreed, McLean, and Shamrock.

In 2015, the Texas Department of Transportation (TxDOT) published the plans for the all new Loop 335 section that will encircle the city of Amarillo.

[5][6] A new mainlane bridge that will accommodate up to six lanes is also in the works for I-40 near Helium Road, providing easier access to the new freeway.