U.S. Route 160 is a 1,465 mile (2,358 km) long east–west United States highway in the Midwestern United States. The western terminus of the route is at U.S. Route 89 five miles (8 km) west of Tuba City, Arizona. The eastern terminus is at U.S. Route 67 and Route 158 southwest of Poplar Bluff, Missouri.

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. McCall's country music song Wolf Creek Pass.

US 160 begins at US 89 near the western edge of Navajo Nation. Near Tuba City, it intersects State Route 264. It goes through Tonalea and Cow Springs before entering Kayenta, where it intersects U.S. Route 163. It continues northeast through Dennehotso, then has a brief overlap with U.S. Route 191 in Mexican Water. 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.

US 160 is one of the major routes crossing the Navajo Nation and in Arizona, does not leave Navajo Nation.

About 0.9 miles (1.4 km) of US 160 is located within New Mexico. The highway travels northeast through extreme northwestern New Mexico, intersecting State Road 597, which provides access to the Four Corners Monument.

U.S. Route 160 enters Colorado near the Four Corners Monument. It goes northeast and intersects U.S. Route 491, then turns north to enter Cortez with U.S. 491. East of Cortez, a road leads south from U.S. 160 to Mesa Verde National Park. It continues east to Durango, where it intersects U.S. Route 550. After overlapping with U.S. 550 south of Durango, U.S. 160 turns east and meets U.S. Route 84 at Pagosa Springs. It then goes northeast and crosses the Continental Divide at Wolf Creek Pass.

From Wolf Creek Pass, U.S. 160 continues northeast and turns east at South Fork. At Monte Vista, an overlap begins with U.S. Route 285, which continues southeast into Alamosa. It turns east, then goes northeast to go through North La Veta Pass, then continues east to Walsenburg, where it intersects Interstate 25.

From Walsenberg, U.S. 160 continues south with Interstate 25 to Trinidad, then turns northeast to intersect U.S. Route 350. It continues east, passing through the Comanche National Grassland before intersecting the concurrent U.S. Route 287 and U.S. Route 385 south of Springfield. It continues east and enters Kansas east of Walsh.

US-160 enters Kansas just west of Saunders. It goes northeast to Johnson, then turns east to go through Ulysses. Near Sublette, it intersects U.S. Route 83 and runs concurrently southward past its intersection with U.S. Route 56. It turns east and then runs concurrently with U.S. Route 54 between Plains and Meade. It continues east, and runs concurrently with U.S. Route 283 and U.S. Route 183. At Medicine Lodge, it intersects U.S. Route 281. It continues east and at Wellington, intersects U.S. Route 81 and then Interstate 35, on which the Kansas Turnpike is routed in the area.

East of Interstate 35, it intersects U.S. Route 77 in Winfield. It goes east from Winfield, then turns north to Burden, then goes east before going south to Elk City. It then turns east and goes through Independence after being concurrent with U.S. Route 75. It continues east, is briefly concurrent with U.S. Route 169 and then intersects U.S. Route 59 at Altamont. US-160 and US-59 then go into Oswego and separate. At Columbus, US-160 begins a concurrency with U.S. Route 69, which goes east to Crestline, then north past Pittsburg to Frontenac, Kansas. Also at Crestline, it picks up a second concurrency with U.S. Route 400, which goes north and ends short of Pittsburg. After Frontenac, it turns east and enters Missouri.

U.S. Route 160 enters Missouri west of Mindenmines. At Lamar, it intersects U.S. Route 71. It goes southeast towards Springfield, where it intersects Interstate 44 and U.S. Route 60, with which it has a short concurrency. It goes south out of Springfield into Nixa as Massey Boulevard, then turns east and intersects U.S. Route 65 north of Branson. It continues east to West Plains, where it intersects U.S. Route 63, then ends southwest of Poplar Bluff at an intersection with U.S. Route 67.

In Willard, Missouri, US 160 runs on a bypass along the western and southern edge of town. The old alignment through Willard is now U.S. Route 160 Business.

As commissioned in 1926 the western terminus was Trinidad, Colorado. In 1939, US 160 absorbed all of former route U.S. Route 450 which ran from U.S. 50 at Crescent Junction, Utah to U.S. Route 85 at Walsenburg, Colorado.

In 1970 many US highways in the Four Corners region were re-aligned. U.S. 160 was diverted southwesterly from Cortez, Colorado to follow its present route past the Four Corners into Arizona, absorbing the route numbered U.S. Route 164 from 1964-1970.

The portion of former US160 (and US450) from Crescent Jct. to Monticello, Utah was replaced with U.S. Route 163 (now U.S. Route 191) and the portion from Monticello to Cortez, Colorado was replaced with U.S. Route 666 (now U.S. Route 491).

The eastern terminus of US 160 was originally located at an intersection with U.S. Route 60 and then-U.S. Route 66 in Springfield, Missouri (Grant Avenue and College Street). In the 1950s, the terminus moved eastward across the state to an intersection with then-US 60 and then-U.S. Route 67 (now Business U.S. Route 60 and U.S. Route 67 Business) in Poplar Bluff. The extension between Springfield and Poplar Bluff was parallel to U.S. Route 65 from Springfield to near Branson, where US 160 then headed east across the Ozark Mountains. 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.

When U.S. Route 160 was formed in Missouri in 1930, it replaced Route 12, which had been created in 1922 as Route 36 from Kansas to Springfield and renumbered in 1926 due to US 36. The 1950s extension absorbed Route 80 (Gainesville to West Plains in 1922, later extended west to Lakeview and east to Thomasville) and the part of Route 14 east of Alton (created in 1922 as Route 42, and later absorbed by Route 14).