It runs 40 miles (64 km) from Perry northwest to the Georgia State Line in Taylor, Madison and Jefferson Counties.

North of the terminus of CR 335, the road narrows down to two lanes at the intersection of US 27, which includes another leg of the truck detour.

The aforementioned G&F Railroad line meets up with the west side of US 221, but runs parallel with it throughout Taylor County, even as they both approach CR 14 (an extension of SR 14) in Shady Grove.

The divided highway ends north of this interchange, and the road continues to wind through the woods of the central Florida Panhandle.

The routes cross the G&F Railroad line it ran next to in Perry and Taylor County on the east side of Leggett Street, and a block later US 221 finally leaves US 90 to run north as it is intended to do.