One segment of 24.13 miles (38.83 km) runs from U.S. Route 412 (US 412) in Siloam Springs east to Interstate 49 (I-49) in Fayetteville.

A second segment of 71.67 miles (115.34 km) runs from I-49 in Fayetteville east to Highway 7 in the Ozark National Forest.

Highway 16 continues southeast, exiting the city and becoming a steep, winding road through the oak-hickory forest.

[3] In Washington County, Highway 16 continues east in the National Forest, serving the Lake Wedington Recreation Area, which contains the Lake Wedington Historic District, and crossing the Illinois River, the eastern boundary of the National Forest, near Savoy.

[5] A focal point of growth in the rapidly developing Northwest Arkansas region, the Wedington Corridor has been subject to much planning and discussion in Fayetteville over the years, subject to biannual neighborhood planning charrettes by a broad group of Fayetteville stakeholders.

[6] The area was annexed into Fayetteville in pieces beginning in 1967, with the combination of a variety of land uses and zonings resulting in rapid growth, heavy traffic congestion, and limited pedestrian facilities.

The highway has a junction with School Avenue (former US 71B), and shortly thereafter a signalized crossing of the Razorback Greenway near Walker Park before continuing east as a two-lane road.

[11] Highway 16 serves as the northern boundary for the White Rock Wildlife Management Area (WMA) within the Ozark National Forest, with access to hunting, fishing, camping, and hiking from various county roads at Dutton, Pettigrew, Boston, and Red Star.

[16] The concurrency ends at Edwards Junction, and Highway 16 continues east through forested land as the northern boundary of the Piney Creeks Wildlife Management Area (WMA), owned by the Arkansas Game and Fish Commission, and passing through Deer before a junction with Highway 7, where it terminates.

[18] The route winds through rural areas, passing through Alread just north of the Gulf Mountain WMA, and ultimately entering Clinton.

An intersection with Highway 330 provides access to Van Buren Recreation Area and the Fairfield Bay Marina on Greers Ferry Lake.

[9][20] Shortly after entering Cleburne County, the route turns south and crosses the upper section of Greers Ferry Lake.

Shortly after entering Cleburne County, the route turns south and crosses the upper section of Greers Ferry Lake.

Highway 16 runs as the northern edge of the town square, passing historic commercial structures, the American Legion Hall, and the Rialto Theater.

After an intersection with Spring Street, Highway 16 passes the historic Cumberland Presbyterian Church and the Jesse N. Cypert Law Office to the north, and the headquarters of First Security Bank to the south.