The western segment of 9.70 miles (15.61 km) runs from Highway 9 in Oxford to Horseshoe Bend.

[1] An eastern segment of 12.65 miles (20.36 km) runs east from U.S. Route 167 in Ash Flat to Arkansas Highway 58.

This segment of highway is named Cardinal Road, and passes through the unincorporated community of Wiseman.

The route winds southeast through Center to meet Arkansas Highway 58, where it terminates.

Highway 354 runs along the southern part of the Harold E. Alexander Wildlife Management Area.