The middle portion of the route, extending 56 miles (90 km) from Ferriday to just north of Mangham, is co-signed with US 425 and is a major four-lane highway through the area.

LA 15 parallels the Mississippi River through a remote rural section of Concordia Parish before reaching junctions with US 84 and US 425 in Ferriday.

The highway passes through the communities of Clayton, Sicily Island, Wisner, and Gilbert before entering the city of Winnsboro.

Just beyond Mangham, at a point known as Archibald, LA 15 turns northwest off of US 425 and proceeds into Monroe, one of northern Louisiana's two metropolitan areas.

West of the city limits, LA 15 turns off of US 80 and heads northwest to Farmerville, situated on Lake D'Arbonne.