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 runs concurrently with I-64 as it enters Kentucky from Indiana, crossing the Ohio River into Louisville on the Sherman Minton Bridge and exiting the I-64 freeway at North 22nd Street in the Portland neighborhood.

The route along Baxter Avenue and Bardstown Road follows the former Louisville and Bardstown Turnpike through the Highlands district of Louisville and past the historic Farmington plantation at the interchange with the Watterson Expressway (I-264).

U.S. routes 150 and 31E separate at Bardstown near the Martha Layne Collins Blue Grass Parkway.

[7] However, in 1976, the decision to truncate US 150 from US 67 in Rock Island to US 6 near the Quad City Airport was approved.

This caused IN 46 to cut back from the Illinois state line to Terre Haute.

[4] U.S. Route 168 was created in 1926 from Louisville to Mount Vernon, Kentucky, overlapping US 68 between Bardstown and Perryville.