U.S. Route 150 (abbreviated Route 150 or U.S. 150) is a 571 mile (919 km) long northwest-southeast United States highway, signed as east–west. It runs from U.S. Route 6 outside of Moline, Illinois to U.S. Route 25 in Mount Vernon, Kentucky .

In the state of Illinois, U.S. 150 runs from the Quad City International Airport at U.S. Route 6 southeast to near Vermilion. U.S. 150 in Illinois is 267.47 miles (430.45 km) long.

Between Moline and Danville, Route 150 closely parallels Interstate 74.

In the state of Indiana, U.S. 150 runs south with U.S. Route 41 from Terre Haute. It is then concurrent with its parent, U.S. Route 50 from Vincennes to Shoals. It then runs east to New Albany before overlapping Interstate 64 into Kentucky. Between Vincennes and New Albany the road follows the original route of the Buffalo Trace.

U.S. 150 runs with I-64 entering Kentucky from Indiana, crossing the Ohio River on the Sherman Minton Bridge. It then forms a major southeastern radial artery from downtown Louisville, called Bardstown Road and intersecting with Interstates 65, 264 and 265.

For its length in Louisville, U.S. 150 is also concurrent with U.S. Route 31E. They separate at Bardstown near the Martha Layne Collins Blue Grass Parkway. U.S. 150 then continues southeast, around the city of Danville before terminating at Mount Vernon.

U.S. Route 168 was created in 1926 from Louisville to Mount Vernon, Kentucky, overlapping US 68 between Bardstown and Perryville. In 1934, US 150 absorbed US 168.

Illinois Route 39 ran from Bloomington to Champaign on the current routing of U.S. 150.