Congestion has become a problem over the years as local government works to develop infrastructure for the growing populations of Orange Park, Middleburg and Green Cove Springs with the northern connectivity sought and thought to be achieved by drastic road widening despite the decimation of Lake Shore's prewar scale.

Residents of both Clay and St. Johns counties' communities rely on Duval's economy (Jacksonville) for employment.

For the first seven miles (11 km), the road is a relatively flat two-lane rural highway heading north with occasional hills, with the only other notable intersection of importance being CR 21, a connecting spur to Marion County.

North of here, the road begins to bear to the northwest, but curves to slightly back along the eastern shore of Lake Melrose.

North of Loch Lommond, SR 21 serves as the southeastern border of Camp Blanding.

In this location, it also runs past Mike Roess Gold Head Branch State Park, and has a short concurrency with CR 315, after turning straight north in Belmore.

Two blocks north of the bridge, the road intersects with the southern terminus of SR 111 (Cassat Avenue).

North of Park Street, Blanding becomes a limited access connecting overpass crossing over Hamilton Street, a double tracked railroad, and has an interchange with US 17 (Roosevelt Boulevard) northbound at the edge of Florida State College at Jacksonville's Kent Campus, also with access from US 17 Roosevelt Boulevard southbound to SR 21 southbound.

The first major intersection it encounters is CR 20A in Johnson, which runs east–west and ends at the southern terminus of SR 21 to the west.

Later it makes another turn to the right onto Cleveland Avenue and heads southeast until finally terminating at SR 21 near Lakeside.