The stretch between Springfield and Decatur is also called Penny Severns Memorial Expressway, and the section between mile 35 and the Mississippi River is known as the Free Frank McWorter Historic Highway.

Its western terminus is an interchange with US 61 to the Mark Twain Memorial Bridge over the Mississippi River.

The portion of I-72 and I-172 from Springfield to Quincy is commonly referred to as the Central Illinois Expressway (CIE).

On June 9, 1991, the American Association of State Highway and Transportation Officials (AASHTO) approved the establishment of I-172 from the western terminus of I-72 at Springfield to Fall Creek, four miles (6.4 km) east of Hannibal, Missouri, though it was contingent on Federal Highway Administration (FHWA) approval.

[2][3] After discussions regarding extending an Interstate Highway through the state of Missouri, on April 22, 1995, AASHTO approved another renumbering.

Signs along the four-lane expressway portion of Mark Twain Avenue marked the route as "Future I-72", while signs along what is now Route 79 had I-72 trailblazers to direct drivers to the temporary terminus at Fall Creek, Illinois.

Based on the 157-mile (253 km) marker at Route 79, if/when US 36 is upgraded to Interstate standards across Missouri, the future western terminus of I-72 would be at Cameron at the intersection with I-35.

There are three exits along this expressway: Veterans Road, Shinn Lane (Hannibal Regional Hospital), and US 24 east at the Rocket Junction.

Due to funding priorities, upgrading US 36 between Macon and Hannibal was a low-priority project and was shelved.

The Missouri Department of Transportation (MoDOT) committed to constructing the four-lane highway as an at-grade expressway only if the five counties served by US 36 east of Macon would contribute half of the $100 million (equivalent to $136 million in 2023[5]) cost.

[8][9] However, in July 2023, the bill was vetoed by Governor Mike Parson who said that it was not the right time to run the study.