U.S. Route 45 (US 45) in the state of Illinois is a major north–south U.S. Highway that runs from the Brookport Bridge over the Ohio River at Brookport north through rural sections of eastern Illinois and then through the suburbs of Chicago to the Wisconsin state line east of Antioch.

The route crosses the Ohio River over the Brookport Bridge, and then curves to the west to travel through downtown Metropolis.

It continues northwest to Vienna, after which it turns to the northeast.US 45 serves as the western boundary of the University of Illinois at Urbana–Champaign campus.

Entering downtown Champaign as Neil Street, US 45 then goes east on Springfield Avenue, running concurrently with US 150.

It also intersects Illinois Route 83 (Calumet Sag Road) for the first time in Palos Hills, just south of the Cal-Sag Channel.

Two miles further north, at Archer, the road loses its 96th Avenue designation; this is due to the road entering suburbs that do not use Chicago's address system, and that most of its alignment north of Archer would be at 10000 W anyway, if the address system extended to these suburbs.

After passing over a Union Pacific rail yard, US 45 becomes concurrent with only US 12 in Melrose Park as US 20 breaks off at Lake Street there.

Near the Northeast portion of O'Hare airport, US 12/45 intersects with Illinois Route 72 in Rosemont, IL, and continues along Mannheim Road into Des Plaines.

The northbound and southbound routes are split in downtown Des Plaines between Lee Street (West 12/North 45) and Graceland Avenue (East 12/South 45).

Just north of US 14, US 12/45 are reunited in both directions on Lee Street, only to be separated as US 12 diverges onto Rand Road and US 45 becomes Des Plaines River Road in a complicated intersection on the north side of Des Plaines, just south of Illinois Route 58.