[1] I-64 enters Illinois running concurrently with I–55 and U.S. Route 40 (US 40) over the Mississippi River on the Poplar Street Bridge.

In Shiloh, the Interstate skirts the northern edge of Scott Air Force Base and MidAmerica St. Louis Airport and provides access to Mascoutah and Lebanon via Illinois Route 4 (IL 4).

A new interchange at Rieder Road was completed in September 2017 to create better access to Scott Air Force Base.

Mount Vernon is the only major city and intersection served by I-64 in Illinois outside of the St. Louis metropolitan area.

[3][1] Past Mount Vernon, the Interstate enters another rural stretch through parts of Jefferson, Wayne, and White counties before crossing the Wabash River into Indiana.