US 63 runs concurrently with US 167 for its entire route in Louisiana, from Ruston north, to Junction City, at the Arkansas state line, a distance of 35 miles (56 km).

[citation needed] U.S. 63 enters into Arkansas from Louisiana concurrent with US 167 in Junction City.

Just a few miles into the state, the two highways run on the eastern edge of El Dorado as an expressway.

Notable routes that are intersected include US 60 in Howell County, I-44 at Rolla, US 50 (with which it shares a concurrency into Jefferson City south of the Missouri River until it reaches the junction with US 54), US 54 (which it overlaps in Jefferson City from the junction with US 50 and crosses the Missouri River with on the Jefferson City Bridge), I-70 at Columbia, US 24 at Moberly, US 36 at Macon, and US 136 at Lancaster.

This segment is an expressway which connects Des Moines with Burlington, with freeway bypasses of Ottumwa and Eddyville.

An expressway section opened in October 2012, completing the four-lane link between Waterloo and New Hampton.

In this area, US 63 is an expressway, but plans are to upgrade the highway to a freeway between Stewartville and the US 52 interchange.

From there, the two routes run concurrently to Red Wing, where US 63 turns north and crosses the Mississippi River to enter Wisconsin over the Eisenhower Bridge.

At Trego, they separate and US 63 runs southwest to northeast, passing through Hayward and Cable most notably, and ending near Ashland at US 2.

Though some maps continued to show this concurrency until 1999, Arkansas had not recognized US 63 south of Turrell for many years, since at least the 1960s.