[5] Upon entering Madison County, the highway intersects Highway 74 in Kingston and passes the Bank of Kingston, a property on the National Register of Historic Places.

The route continues north through Carroll County and enters Berryville, before a brief concurrency with US 62, followed by a concurrency with Highway 221, after which it heads north to the Missouri state line, where it continues as Missouri Route 13.

[7] The byway begins at the southern terminus of Highway 21 at US 64 in Clarksville and runs north to the Buffalo National River near Boxley.

[7] The highway is popular as a major route to the Ozark National Forest, the Ozark Highlands Trail, and the White River in addition to being the major travel route to cities in the area and points in southern Missouri.

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