The entire route is overlapped with SR 34, save for approximately a half mile between US 11E/US 19 and the Virginia State Line.

The highway then goes northwest to enter the oldest unincorporated community in the state, Trade, where it begins an unsigned concurrency with SR 67.

The highway continues northwest through countryside and farmland before becoming the eastern boundary of the Cherokee National Forest at the intersection of Bulldog Road before completely entering the National Forest after the intersection with Old Prison Camp Road.

The highway then passes through more countryside and farmland before the road becomes aggressively curvy with elevation changes throughout as it crosses the Iron Mountains, where the road becomes aggressively curvy with elevation changes throughout for several miles.

This is the second stretch of aggressively curvy with constant elevation changing along US 421, with this whole section, between Mountain City and Holston Valley, being very popular with motorcycle enthusiasts.