U.S. Route 431 is a spur of U.S. Route 31. It currently runs for 556 miles (895 km) from Owensboro, Kentucky at U.S. Route 60 to Dothan, Alabama, at U.S. Route 231 and U.S. Route 84. Through many parts of US 431 it is a two lane with not many places of it being a four lane highway.

U.S. 431 is paired with unsigned State Route 1 throughout almost all of Alabama, with the exception Dothan, where it is paired with unsigned State Route 210. Within Dothan, AL 1 is also paired with US 231 between the Florida State Line and the Dothan Loop, and US Business Routes 231 and 431 in Dothan, Alabama.

U.S. 431 enters the state of Kentucky south of the town of Adairville, Kentucky where it runs north into Russellville, Kentucky. It continues through Russellville, Kentucky northbound where many new re-construction projects have widened it to a 4-Lane highway. U.S. 431 continues its northward journey passing through many small towns when it enters Drakesboro, Kentucky. After routing through Drakesboro, Kentucky, U.S. 431 follows most of its original route into Central City, Kentucky. In Central City, Kentucky U.S. 431 has a cloverleaf intersection (a former toll plaza when the parkway was toll) with the Western Kentucky Parkway. 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, Kentucky. A portion of this route is named Everly Brothers Boulevard because the duo is originally from Central City, Kentucky. U.S. 431 turns north at the State Route 189 & U.S. 62 Bypass and continues on through many small farming communities of Muhlenberg County, Kentucky & McLean County, Kentucky. It bisects many rural rolling hills and farms of the Western Coal Fields as well as crosses through river lowlands of the Ohio Valley on its journey to Daviess County, Kentucky. It enters the city of Owensboro, Kentucky as a 4-Lane highway and one of the main arterial roads into the city. Many shopping centers reside along its outer reaches in Owensboro, Kentucky.

As of mid-2010, U.S. 431 now officially terminates at the former US 60 By-Pass (Wendell H. Ford Expressway) on Owensboro's south side, following AASHTO's approval of Kentucky's renumbering of the US 60 By-Pass as simply U.S. 60. The former route of U.S. 60 through downtown Owensboro (Second and Fourth streets) is to be turned over to the city and made more "pedestrian-friendly" as part of the city's latest downtown revitalization plan.

In early 2011, the Kentucky Transportation Cabinet renumbered the former section of U.S. 431 from U.S. 60 to Fifth Street in Owensboro as Kentucky State Route 2831.

A small portion of U.S. 431 is famous for a unique reason. U.S. 431 crosses the Green River in McLean County, Kentucky. It is at that crossing in the town of Livermore, Kentucky that U.S. 431 crosses two rivers and also crosses into Ohio County, Kentucky then terminates the river crossing back in McLean County, Kentucky. This is the only known crossing of this type in the United States where a road starts in a county, crosses two separate rivers, crosses a sliver of land that is part of another county, and then terminates the bridge crossing in the original county it started in. This special feature is marked by a Kentucky Historical Marker on both approach ends of the U.S. 431 bridge in Livermore, Kentucky.

U.S. Route 241 was created in 1930, splitting from US 41 in Murfreesboro, Tennessee and heading south to US 231 in Dothan, Alabama. The route of the highway, starting at Murfreesboro, TN, went south through Shelbyville and Fayetteville to Huntsville. From Huntsville, the highway snaked through Owens Cross Roads and New Hope (on a road currently named "Old Highway 431") on its way to Guntersville, then through Albertville and Boaz (on what is now AL 205) on its way to Gadsden, then to Anniston and Oxford. After US 231 was extended through north Alabama and Tennessee through Huntsville to Murfreesboro around 1952, the northern terminus of US 241 became Huntsville. In 1953, since US 241 began and ended in Alabama, it was decommissioned. However, US 431 was being extended southward from Kentucky through Tennessee and Alabama, so the lost section from Huntsville to Oxford gained the US 431 designation. However, from Oxford, the US 241 route ran through Talladega, Sylacauga, Goodwater, Alexander City, and Opelika, but US 431 was not routed onto this section, but onto the AL 37 route, which was a shorter route to Opelika. However, the Sylacauga to Opelika section did gain the US 280 designation. From Opelika, US 241 ran south to Phenix City and this section gained the US 431 designation.