U.S. Route 64 (US-64) is a U.S. highway running from the Four Corners area to the Outer Banks of North Carolina. Between these two points, the highway passes through the entire width of Oklahoma; a total of 591.17 miles (951.40 km) of US-64 lies in the state of Oklahoma. US-64 enters the state from New Mexico, crossing the line between the two states between Clayton, New Mexico, and Boise City in Cimarron County. The route runs the full length of the Oklahoma Panhandle, then serves the northernmost tier of counties in the main body of the state before dipping southeastward to Tulsa, the state's second-largest city. From Tulsa, the highway continues southeast, leaving Oklahoma just west of Fort Smith, Arkansas. In addition to Tulsa, US-64 serves fifteen Oklahoma counties and the cities of Guymon, Woodward, Enid, and Muskogee.

The United States Numbered Highway System is an integrated network of roads and highways numbered within a nationwide grid in the contiguous United States. As the designation and numbering of these highways were coordinated among the states, they are sometimes called Federal Highways, but the roadways were built and have always been maintained by state or local governments since their initial designation in 1926.