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Upon entering Kentucky, U.S. 60 is concurrent with U.S. 51 and U.S. 62 from the Ohio River bridge to the town of Wickliffe. At Wickliffe, U.S. 60 separates from the other routes and heads generally northeast toward the city of Paducah. Between Wickliffe and Paducah, the towns of Barlow, La Center and Kevil are situated along the route.

Upon reaching Paducah, U.S. 60 intersects with Interstate 24, and I-24's business loop enters the city concurrent with U.S. 60. In the downtown area, the route once again meets U.S. 62, and also meets U.S. 45. Once out of the city of Paducah, U.S. 60 again veers to the northeast, generally following the Ohio River until reaching Smithland, where the route again turns to the east, passing through the small town of Burna. From Burna, U.S. 60 passes through Salem.

The next city along the route is Marion. At Marion, U.S. 60 turns once more to the north, where it heads toward Sturgis. From Sturgis, the route continues generally northward to Morganfield. In recent years, a by-pass of U.S. 60 around the south and east sides of Morganfield has taken a great deal of traffic out of Morganfield proper.

U.S. 60 passes through Waverly and Corydon before reaching Henderson. At Henderson, the route intersects Kentucky Highway 136, Kentucky Highway 425 and U.S. Highway 41 Alternate. U.S. 41-A is concurrent with U.S. 60 along Green Street in the city of Henderson as it intersects with Kentucky Highway 812 and Kentucky Highway 351. At the U.S. Highway 41/Pennyrile Parkway interchange, U.S. 41-A ends and U.S. 60 continues alone, going through Owensboro, Hawesville, and Hardinsburg.

In Fort Knox, U.S. 60 connects with U.S. 31W, and they remain together until downtown Louisville. Originally built as a "bypass route" around downtown Louisville, Kentucky, Alt US 60 used several existing roads running through Louisville to get between the east and south sides of town without having to travel through the heavily congested downtown or west ends of town. 'Alt 60' runs northeast to southwest from St. Matthews, Kentucky to Shively, Kentucky; including a stretch on one of Frederick Law Olmsted's last remaining parkways, Eastern Parkway.

After passing Shelbyville, it continues through the state capitol in Frankfort. In Versailles, its eastbound lanes are the westbound lanes of U.S. 62. After intersecting the Bluegrass Parkway, it is one of the major routes through Lexington. It intersects I-75 and goes to Winchester and the Mountain Parkway. It proceeds to Mount Sterling, Morehead, past Carter Caves, on to Grayson and finally to Ashland. U.S. 23 South follows U.S. 60 East into Catlettsburg, where they split at 35th St. U.S. 23 South continues straight as a 4-lane highway, while U.S. 60 East turns left on 35th St., passes Oakland Avenue, and enters Kenova, West Virginia via the Billy C. Clark Bridge.

Especially in the eastern and central part of the state, U.S. 60 has been largely replaced by Interstate 64 for long distance travel, since both routes follow each other through much of this area. However, several cites in this area rely on U.S. 60 to connect them to the interstate. By contrast, in the western part of the state, U.S. 60 is not paired with an interstate highway and serves a much more independent purpose, connecting communities located along and near the Ohio River.

Preceded by Illinois

U.S. Route 60 Kentucky

Succeeded by West Virginia