The western terminus of the route is at US 89 five miles (8.0 km) west of Tuba City, Arizona.

Its route, if not its number, was made famous in song in 1975, as the road from Wolf Creek Pass to Pagosa Springs, Colorado in C.W.

It goes east until Teec Nos Pos, where it intersects U.S. Route 64, then turns northeast to go to the Four Corners and enters New Mexico.

The highway travels northeast through extreme northwestern New Mexico, intersecting State Road 597, which provides access to the Four Corners Monument.

East of Cortez, a road leads south from U.S. 160 to Mesa Verde National Park.

After overlapping with U.S. 550 south of Durango, U.S. 160 turns east and meets U.S. Route 84 at Pagosa Springs.

From Wolf Creek Pass, U.S. 160 continues northeast and turns east at South Fork.

From Walsenburg, U.S. 160 continues south with Interstate 25 to Trinidad, then turns northeast to intersect U.S. Route 350.

At Columbus, US-160 begins a concurrency with U.S. Route 69, which goes east to Crestline, then north to Frontenac, Kansas.

Also at Crestline, it picks up a second concurrency with U.S. Route 400, which goes north and ends just south of Pittsburg, Kansas.

It goes southeast going through Greenfield and Willard before passing through Springfield, where it intersects Interstate 44 and U.S. Route 60, with which it has a short concurrency with the latter.

It goes south out of Springfield into Nixa as Massey Boulevard, then turns east and intersects U.S. Route 65 north of Branson.

[7] In 2007, the terminus was moved to its current location southwest of Poplar Bluff, eliminating a concurrency between US 160 and two other highways (US 67 and US 67 Business) over the last 10 miles (16 km) of US 160.

It crosses the Los Pinos River and runs north of downtown until it reaches its eastern terminus at US 160.

It runs along Jackson Street from US 160 northwest of Willard and through downtown before it terminates at US 160 southeast of town.