U.S. Route 64 (US 64) is an east–west United States highway that runs for 2,281 miles (3,672 km) from Nags Head in eastern North Carolina to just southwest of the Four Corners in northeast Arizona.

Major cities served along US 64's route include Tulsa, Oklahoma, Conway, Arkansas, Memphis and Chattanooga, Tennessee, and Raleigh and Rocky Mount, North Carolina.

From there, it runs southeast through sparse ranch land for about 4.16 miles (6.69 km) to the New Mexico state line.

Heading into the Oklahoma Panhandle, the three conjoined routes pick up a fourth two miles (3 km) southwest of Boise City, as US-385 merges from the south.

Shortly thereafter, US-56 also departs the route, heading northeast into Kansas, while US-64 and US-412 continue their journey due east toward Guymon.

These two routes remain together for about 20 miles (32 km), splitting at Hooker, with US-54 continuing northeast into Kansas while US-64 again veers due east.

Twenty miles (32 km) to the east, US-270 departs to the south, and US-64 finally runs solo for a significant stretch save for very short concurrencies with US-283 near Rosston, US-183 through Buffalo, and US-281 in Alva.

The two routes remain together until they meet Interstate 35, which US-64 joins briefly southbound while US-412 continues east, becoming the Cimarron Turnpike.

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 US-59), Muldrow, and Roland before leaving the state.

The route traverses several streets in Memphis before becoming a rural divided highway in eastern Shelby County.

US 64 then continues on past Lawrenceburg, the largest city on the Alabama state line between Memphis and Interstate 65, to Chattanooga.

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

It is the longest highway in North Carolina; a common way to express coverage of the entire state is to say, "from Murphy to Manteo".