Route 5 enters Douglas County 0.6 mi (0.97 km) north of Wasola.

Shortly after entering Wright County, Route 5 forms a one-mile east–west concurrency with U.S. 60 (as a limited-access highway) in Mansfield.

Between Lebanon and Camdenton, the road has been realigned and straightened, and several older alignments are visible.

In Cooper County, Route 5 continues north for 20 miles before intersecting I-70 just south of Boonville.

Thirteen miles to the north of the Chariton County line, Route 5 forms a five-mile east–west concurrency with U.S. 24 and enters Keytesville, where it leaves the concurrency to the north and enters Linn County 21 miles later.

[5] As built in the original 1922 road system, the route is largely unchanged from its first path.

[6] In the 1950s a section of the route in Wright, Douglas and Ozark counties between Mansfield and Gainesville was straightened and widened.

[8] Beginning in the summer of 2008, MoDOT began a project to convert Route 5 into a "shared four-lane" highway, with continuous passing lanes based on the European 2+1 road model,[9] between Lebanon and Camdenton.

A number of roadways in Europe are built in this way, but Missouri is among the first to do so in the U.S., having first used the method on separate segments of US 63 and Route 37.

The project was completed in 2010 for the Camden County section, it was built on a new realignment to bypass the existing alignment.