It runs from U.S. Route 30 (US 30) in Frankfort north to the large intersection of IL 120 (Belvidere Road) and US 41 (Skokie Highway) in Waukegan.

IL 43 is called Waukegan Road for the first 20 miles (32 km) until its intersection with Oakton Street in Niles; it then follows that road west one block until it turns back south and remains Harlem Avenue for the duration.

It enters, exits, and runs parallel to Chicago limits several times, passing through or parallel to Edison Park, Norwood Park, Dunning, Montclare, and Austin on the Northwest Side then Garfield Ridge and Clearing on the Southwest Side.

[5] In 1967, Illinois Route 42A, which originally followed Waukegan Road and Harlem Avenue, was decommissioned and was replaced by IL 43.

[2][6] In Deerfield, IL 43 is designated a Blue Star Memorial Highway.