U.S. Route 40 (US 40) runs east–west across south central Illinois for 159.8 miles (257.2 km).

US 40 enters the state from Missouri across the Poplar Street Bridge over the Mississippi River at East St. Louis concurrent with Interstate 55 (I-55) and I-64 and exits just south of State Line, Indiana, running concurrently with I-70.

For nearly its entire route, US 40 is two-lane and rural, with the exception of portions in and around major towns and cities.

Just east of the bridge, the three routes run concurrently with IL 3 as well as the Great River Road.

At a trumpet interchange 17 miles (27 km) from the Missouri state line, US 40 branches off from I-55 and I-70.

[2] Up until 1935, Illinois Route 11 (IL 11) roughly followed the old alignment of US 40 from St. Louis to near Terre Haute, Indiana.

[4] But in the mid-1940s, IL 11 was reused after US 40 was realigned south of downtown Greenville and Mulberry Grove, Illinois.