U.S. Route 64 is a U.S. highway running from Teec Nos Pos, Arizona east to Nags Head, North Carolina. In the U.S. state of Arkansas, the route runs 246.35 miles (396.46 km) from the Oklahoma border in Fort Smith east to the Tennessee border in Memphis. The route passes through several cities and towns, including Fort Smith, Clarksville, Russellville, Conway, Searcy, and West Memphis. US 64 runs parallel to Interstate 40 until Conway, when I-40 takes a more southerly route.

Fort Smith is the third-most populous city in Arkansas, United States, and one of the two county seats of Sebastian County. As of the 2020 census, the population was 89,142. It is the principal city of the Fort Smith, Arkansas–Oklahoma Metropolitan Statistical Area, a region of 298,592 residents that encompasses the Arkansas counties of Crawford, Franklin, and Sebastian, and the Oklahoma counties of LeFlore and Sequoyah.