The highway's eastern terminus is in Hudson Oaks, Texas (west of Fort Worth, near Weatherford), at an intersection with Interstate 20.

However, no signage along the route exists past this intersection until SR 64 turns east towards Cameron, Arizona.

In Flagstaff, US 180 is concurrent with Interstate 40 Business and historic U.S. Route 66 for a short distance through the city.

Shortly after following South Navajo Boulevard, however, US 180 follows a south-southeast route, running by the Petrified Forest National Park and continuing South-Southeast to and through a small branch of the Zuni Indian Reservation, to St. Johns, Apache County, Arizona where it meets U.S. Route 191.

On the east side of Springerville US 60 leaves the concurrency and US 180 and US 191 head south through Eagar, Arizona where the two routes enter the Apache National Forest and finally split at the town of Alpine, Arizona, roughly 6 miles from the Arizona-New Mexico border.

US 62/180 then travels east, going past the spur RM 2775 (which goes north to Hueco Tanks) through the southern end of the Guadalupe Mountains National Park (90 miles east of El Paso), and past the southern face of Guadalupe Peak (the highest point in Texas) towards New Mexico and Carlsbad Caverns National Park.

US 180 continues eastward running through the towns of: Lamesa, Gail, Snyder, Roby, Anson, Albany, and Breckenridge.

For the last portion of its length, the road runs through the scenic Palo Pinto Mountains, exiting them at Metcalf Gap.

[3] Towns in this final portion include Palo Pinto, Mineral Wells and Cool.

On January 19, 1935, US 260 was extended eastward to US 80 near Deming, New Mexico, establishing a concurrency with US 666 from Springerville to Alpine in Arizona.

The American Association of State Highway Officials (AASHO) was willing to approve the request but recommended the route be re-designated with a different number.