Highway 21 is a north–south state highway in north central Arkansas. The route of 99.14 miles (159.55 km) runs from US Route 64 (US 64) in Clarksville north across US 62 to Missouri Route 13 at the Missouri state line The route is a two-lane highway with the exception of a brief concurrency with US 62, a four-lane highway, in Berryville.

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.