U.S. Federal Route 150 runs north-south in the north-central portion of Knox County. At Vincennes this highway turns and runs east-west. U.S. Rt. 150 does not pass through any towns in Knox County. U.S. Rt. 150 is multi-plexed in Knox County. U.S. Rt. 41, from the Knox/Sullivan County Line to east of Vincennes.
U.S. Rt. 50, from north of Vincennes to the Knox/Daviess County Line.