The route is maintained by the Arkansas State Highway and Transportation Department (AHTD).

Highway 221 begins at the Madison County line in the Ozark Mountains.

County Road 1425 continues south from this terminus into the McIlroy Wildlife Management Area under the Arkansas Game and Fish Commission administration.

Highway 221 winds through rural areas toward the state line, where the roadway continues as Missouri Route 39 towards Springfield.

[1] It was extended south on November 23, 1966, between US 62 in Berryville and the Madison County line.