The major cities US 431 connects to (from south to north) are Dothan and Huntsville, Alabama, Franklin and Nashville, Tennessee, and Owensboro, Kentucky.

The southern terminus of US 431 is at the intersection of US 231 and the business spurs on the south side of Ross Clark Circle.

From here, US 431/SR 50 travels through mountainous and largely undeveloped territory in south central Tennessee until arriving in Lewisburg.

Meanwhile, SR 50 splits off to travel through downtown Lewisburg, rejoining US 431 on the north side of town.

The route skirts the campus of Vanderbilt University before entering downtown Nashville from the southwest.

Crossing under Interstate 40 (where SR-106 ends), the route follows Broadway to its intersection with Rosa L. Parks Boulevard.

The route snakes around the state capitol and crosses the Cumberland River going northwest as James Robertson Parkway.

In east Nashville, the route crosses under Interstate 24, then follows Spring Street and then Dickerson Pike northward.

U.S. 431 continues its northward journey passing through many small towns when it enters Drakesboro, after which it follows most of its original route into Central City.

The route continues north and intersects with U.S. 62 where it then parallels the route in a westerly direction to a western bypass around the central business district of Central City, in which city it is named in honor of the Everly Brothers, locally-born prominent singers.

U.S. 431 turns north at the Kentucky Route 189 and U.S. 62 bypass and continues on through many small farming communities of Muhlenberg and McLean counties.

After bisecting many rural rolling hills and farms of the Western Coal Fields as well as crossing through river lowlands of the Ohio Valley on its journey to Daviess County, it enters the city of Owensboro as a four-lane highway and one of the main arterial roads into the city.

This special feature is marked by a state historical marker on both approach ends of the bridge.

Around 1952, the terminus was truncated and the route was extended north, entering Tennessee and went through Fayetteville and ended up in Shelbyville.

US 431 from South Carrollton to Owensboro was originally signed as Kentucky Route 75 (KY 75) from its 1929 establishment until US 431 replaced the designation in 1953.