The road enters the state (passing the Oregon County line) at Thayer.

The highway then enters Phelps County and passes through Rolla, the home of Missouri University of Science and Technology, and becomes locally known as Bishop Avenue.

There is no direct connection between Route 63 and I-70; access to and from the Interstate is via an at-grade connector road, which intersects I-70 at a simple Diamond interchange.

Through town, the highway narrows to a two-lane city street, with a center left-turn lane.

Near the northern edge of town, US 63 intersects US Route 36, which is part of the Chicago-Kansas City Expressway.

Leaving Macon, the highway re-gains expressway status, and passes by La Plata before crossing into Adair County.

Leaving the Kirksville bypass, US 63 returns to a two-lane surface highway, and enters Schuyler County.