U.S. Route 64 is an east–west United States highway that runs for 2,326 miles (3,743 km) from eastern North Carolina to just southwest of the Four Corners in northeast Arizona. The western terminus is at U.S. Route 160 in Teec Nos Pos, Arizona. The highway's eastern terminus is at NC 12 and U.S. Route 158 in Nags Head, North Carolina.

U.S. 64's western terminus is Teec Nos Pos, Arizona, at U.S. Route 160. It goes southeast from Teec Nos Pos and enters New Mexico.

U.S. 64 runs through Farmington, Taos, Cimarron, and Raton. As it runs through Raton, it is co-signed with U.S. Route 87. It continues through to Clayton, where U.S. 87 is replaced by U.S. Routes 56 and 412. The three routes then run concurrently into Oklahoma. Twenty-eight miles east of Cimarron is Raton Municipal Airport.

Heading into the Oklahoma Panhandle, the three conjoined routes pick up a fourth two miles (3 km) southwest of Boise City, as U.S. 385 merges from the south. In Boise City, U.S. 385 departs to the north along with U.S. 287, which replaces U.S. 385 in the four-way concurrency on the way out of town to the east, before departing itself to the southeast two miles (3 km) outside of town. Shortly thereafter, U.S. 56 also departs the route, heading northeast into Kansas, while U.S. 64 and U.S. 412 continue their journey due east toward Guymon.

Near Guymon, the route turns due south to approach the town. U.S. 412 then heads due east, while U.S. 64 veers from due south to northeast, joining up with U.S. 54. These two routes remain together for about 20 miles (32 km), splitting at Hooker, with U.S. 54 continuing northeast into Kansas while U.S. 64 again veers due east. At Turpin, U.S. 64 turns left, running north with U.S. 83; three miles (5 km) later, it again turns east, joining U.S. 270 while U.S. 83 and westbound U.S. 270 continue north to Liberal, Kansas. Twenty miles to the east, U.S. 270 departs to the south, and U.S. 64 finally runs solo for a significant stretch save for very short concurrencies with U.S. 283 near Rosston, U.S. 183 through Buffalo, and U.S. 281 in Alva.

Near Pond Creek, U.S. 64 turns south, joined by U.S. 60 and U.S. 81. U.S. 64 splits off just north of Enid, jogging through the city before rejoining U.S. 412 on the east side of town. The two routes remain together until they meet Interstate 35, which U.S. 64 joins briefly southbound while U.S. 412 continues east, becoming the Cimarron Turnpike. U.S. 64 departs I-35 at Perry, intersecting the parallel U.S. 77 before continuing east.

On either side of Morrison the route intersects U.S. 177 and U.S. 412 (again) before passing through Pawnee and Cleveland. It then veers southeast, rejoining U.S. 412 yet again to head into Tulsa.

In downtown Tulsa, the route diverges from U.S. 412 for the final time. It shares pavement briefly (and separately) with Interstate 244 and U.S. 75 before bearing southeast through the city, intersecting Interstate 44 before briefly joining the southernmost five miles (8 km) of U.S. 169 running southbound on the eastern edge of the city. It then proceeds south, crossing the Creek Turnpike, then crosses the Arkansas River in Bixby before turning to the southeast.

After passing through Haskell, U.S. 64 and U.S. 62 meet head-on, north–south; they join and head east toward Muskogee. The routes disengage at the intersection with U.S. 69, with U.S. 64 bearing south out of the center of town. At Warner, the route turns eastward again, where it will run parallel to Interstate 40 for the remainder of its path through Oklahoma. It passes through Webbers Falls, Gore, Vian, Sallisaw (where it has a brief concurrence with U.S. 59), and Muldrow, before leaving the state.

The route enters Arkansas in Fort Smith and crosses the Arkansas River. The route continues following Interstate 40 through Clarksville, Russellville, and Conway, where I-40 turns south an US 64 continues east. US 64 runs with US 67 and US 167 near Searcy before passing through rural Eastern Arkansas fields. US 64 runs east to Marion and West Memphis, where it meets I-40 and Interstate 55 to continue east over the Mississippi River on the Memphis & Arkansas Bridge to Memphis, Tennessee. A segment of US 64 in Crittenden County is also known as Military Road and is the oldest road in the state. It was surveyed for the removal of Native Tribes known of as the Trail of Tears. A historical marker in Marion notes this information.

US-64 enters Tennessee on the Memphis-Arkansas Bridge at Memphis. The route shares the bridge with Interstate 55 and U.S. Highways 61, 70, and 79. The route traverses several streets in Memphis before becoming a rural divided highway in eastern Shelby County. The highway runs directly to the east through the county seats of Tennessee's most southern counties before entering Chattanooga. U.S. 64 runs from Chattanooga to Cleveland, where it duplexes with US-74 to the North Carolina state line. The Tennessee Department of Transportation is currently working to expand the highway to four lanes across the state. The easternmost portion of the highway in Tennessee is the Ocoee Scenic Byway, a winding, two-lane road through the Ocoee River gorge in Polk County. The steep terrain around the highway is subject to landslides, such as the massive slide in November 2009 that closed the highway for several months.

US 64 enters North Carolina in Cherokee County, west of Murphy. The highway serves the cities of Hendersonville, Brevard, Rutherfordton, Lenoir, Statesville, Lexington, Asheboro, Siler City, Cary, Raleigh, Rocky Mount, Tarboro, Williamston, and Manteo.

The segment from Franklin to Highlands is a mountainous two-lane road limited to moderate-sized trucks. Large trucks are routed via Truck US 64 (US 23/441 and US 74) to Sylva, and Asheville.

Interstate 40 travels through Statesville on a route originally designed in 1950 as a bypass of US 64, intersecting with Interstate 77 at what was once intended to be a bypass of US 21.

Within the Raleigh city limits US 64 follows the southern section of the Beltline. In 2006 a major section known as the Knightdale Bypass opened to ease traffic. After it was completed, US 64 became a divided freeway between Cary and Williamston, and carried at least four lanes between Asheboro and Columbia.

US 64 serves as a gateway to the Outer Banks, ending at Nags Head where it meets U.S. Route 158 and NC 12.

Overall, US 64 runs more than 600 miles (970 km) from the Western edge of the state to the Outer Banks. It is the longest highway in North Carolina. In North Carolina, the common way to express coverage of the entire state is to say, "from Murphy to Manteo." US 64 runs through both.

U.S. Route 485 was commissioned in 1926, looping west of US 85 between Santa Fe and Raton, New Mexico. In 1931, it became an extension of US 64. In 1959, the Arizona Department of Transportation submitted a proposal to extend US 64 west from Santa Fe, New Mexico to US 89 near Tuba City, Arizona, which was rejected. The portion south of Taos was removed in 1974, when US 64 was realigned and extended to Farmington, and became NM 68.

There are several sections of Business US 64 serving more as alternate routes of the main highway. While they go through towns and cities, they often run numerous miles through rural areas and often pass through more than one city.

U.S. Route 64 in Cimarron, New Mexico.

US-64 in Woods County, Oklahoma.

US64/US70/US79 overlap in Memphis, Tennessee (2008).

U.S. Route 64 near Siler City, North Carolina.