In the U.S. state of Illinois, U.S. Route 50 is an east–west highway across the southern portion of the state. It runs from the Jefferson Barracks Bridge over the Mississippi River to Missouri east to the Red Skelton Memorial Bridge over the Wabash River to Indiana. This is a distance of 165.79 miles (266.81 km).

U.S. 50 runs east–west across the southern portion of the state, between Interstate 70 to the north and Interstate 64 to the south. Along many portions of U.S. 50, the road has been moved onto either a bypass or an expressway.

Much of U.S. Route 50 in Illinois, especially the section between Carlyle, Illinois and Vincennes, lies atop or adjacent to the trail taken by George Rogers Clark and his 170 volunteers in the forlorn-hope march on Vincennes in February 1779.

As of 2011, much of U.S. 50 is a two-lane highway, but portions around Lawrenceville, IL and Vincennes, IN are configured as a four-lane, limited access bypass, built to interstate standards in the 1960s. Another modern bypass portion between O'Fallon, IL and IL-127 shows evidence of a four-lane right of way as each bridge is paralleled by a second that remains unused and the graded road bed for additional lanes is visible. This is because it was originally meant to be the route of Interstate 64 until political leaders lobbied for and secured a more southerly route.