After entering the state from neighboring Kansas, the route moves eastward through many rural towns and communities.

It passes through Nevada, where it serves as the main access road to the town's business market.

Moving eastward, the route continues through El Dorado Springs, Collins, Weaubleau, and Wheatland, the latter is home of the Lucas Oil Speedway.

The route then briefly enters Lake Ozark and Lakeland, although access to these towns is only provided by exits from the highway.

The route then leaves the Lake of the Ozarks after crossing the Osage River before bypassing Eldon.

Future plans call for passing lanes on US 54 from Mexico to the Missouri town of Louisiana.

North of Laddonia, US 54 splits from Route 19 before passing just north of Vandalia, bypasses Bowling Green crossing US 61, and ultimately crossing the Mississippi River via the Champ Clark Bridge into Illinois at Louisiana.