The second segment begins on the Texas state line between Hobbs, New Mexico, and Seminole and travels east across the lower Panhandle and Cross Timbers regions, passing through the towns of Lamesa, Snyder, Albany, and Breckenridge.

I-10/US 180 run along the northern edge of downtown El Paso together, with US 180 leaving and joining U.S. Route 62 at Paisano Drive.

The highways run along the southern border of El Paso International Airport and Fort Bliss, before intersecting with Loop 375, leaving the city shortly thereafter.

US 180 continues to run in a predominantly east–west direction through northwest Texas, passing through towns such as Breckenridge and Mineral Wells.

A section of US 62/US 180 in eastern El Paso, known locally as Montana Avenue, is currently being upgraded to a six-lane freeway.