In the U.S. state of Illinois, U.S. Route 12 is an arterial highway that runs northwest to southeast through the Chicago metropolitan area. It enters Illinois at the Wisconsin border north of Richmond, and exits into Hammond, Indiana from Chicago near the foot of the onramp to the Indiana Toll Road (Interstate 90); as it exits Illinois, the route is also concurrent with U.S. Routes 20 and 41. Within Illinois, U.S. Route 12 runs for a distance of 85.14 miles (137.02 km).

The westernmost portion of U.S. 12 in Illinois runs south from the Wisconsin border, between Genoa City, Wisconsin and Richmond. North of Genoa City, U.S. 12 is a four-lane limited-access freeway. In Illinois, it reverts to a two-lane, undivided surface road prior to a traffic light with Illinois Route 173 north of Richmond. South of Richmond, through traffic on U.S. 12 must turn left at Illinois Route 31 to continue. until the Fox Lake area; at that point it becomes a four-lane divided highway, with occasional interchanges.

U.S. 12 overlaps Illinois Route 59 south of Fox Lake at an access-controlled interchange, and then intersects with Illinois Route 134 at a traffic light. In Volo, there is a traffic light with Illinois Route 120, but then reverts to an expressway, having interchanges with Illinois Route 176 (Liberty Street) and Illinois Route 59. From the state line to this point, U.S. 12 is also marked as the main route for the Fox River Valley, which continues south on Illinois 59.

In Lake Zurich, U.S. 12 picks up the name Rand Road, named so for a former name of the city of Des Plaines. There is also an intersection with Illinois Route 22 (Main Street). U.S. 12 proceeds towards Deer Park and Kildeer before entering Cook County in Palatine. U.S. 12 then briefly overlaps Illinois Route 53 between Hicks Road and Illinois Route 68 (Dundee Road) in northeast Palatine. At the expressway portion of Illinois 53, U.S. 12 traffic can only access southbound Illinois 53.

From Illinois 53, U.S. 12 travels through the heavily populated areas of Arlington Heights and Mount Prospect, intersecting with Illinois Route 83 (Elmhurst Road) in Mount Prospect. U.S. 12 enters the Des Plaines area at Illinois Route 58 (Golf Road), and joins with U.S. Route 45 (Des Plaines River Road) north of downtown at a complex intersection. Westbound U.S. 12 traffic is required to cross U.S. 45 twice (on Elk Boulevard) to access Rand Road, as all turns are prohibited from U.S. 45 to U.S. 12. Eastbound U.S. 12 joins with southbound U.S. 45.

In Des Plaines, U.S. 12/45 separate, as southbound traffic travels on Graceland Avenue, while northbound traffic runs one block east. In downtown Des Plaines, U.S. 12/45 has a major intersection with U.S. Route 14 (Miner Street) at a busy Metra railroad crossing.

After turning south from Des Plaines, U.S. 12 and 45 form a major north–south artery through the western suburbs. North of Cermak Road the route is known as Mannheim Road, while south of Cermak Road it is known as La Grange Road. The distance from the intersection of U.S. 12/45 and U.S. 14 in Des Plaines to the U.S. 12/20/45 split in Hickory Hills is 9.97 miles (16.05 km).

U.S. Routes 12 and 45 run through various streets in Des Plaines before aligning along Mannheim Road north of O'Hare International Airport. This routing also closely parallels the Metra North Central Service line to Antioch. U.S. 12/45 intersect Illinois Route 72 (Higgins Road) at the northeast corner of the airport, and then travels south along the eastern border of the airport. There is a full interchange with Interstate 190 for passenger airport traffic. At the southeast corner of the airport, a signalized intersection terminates a brief expressway portion of Illinois Route 19 (Irving Park Road).

South of Irving Park Road, U.S. 12/45 travels beneath the Bensenville Bridge on Interstate 294 (Tri-State Tollway) while also crossing over the Franklin Park rail yard; however, there is no interchange with I-294 at this point. This rail line also carries Metra Milwaukee District West trains. In Melrose Park, U.S. 12/45 has a grade-separated intersection with Illinois Route 64 (North Avenue), a major east–west artery west of Chicago. About a mile (1.6 km) south, U.S. 20 joins with U.S. 12/45 to form a triple concurrency over a set of Union Pacific tracks.

U.S. 12/20/45 continues south and becomes the eastern endpoints of two Illinois State Routes: Illinois Route 56 in Bellwood and Illinois Route 38 in Westchester. In between lies a full intersection with Interstate 290 (Eisenhower Expressway). In downtown La Grange, U.S. 12/20/45 intersect with U.S. Route 34 (Ogden Avenue), making it the only location in the Chicago area (and possible the state of Illinois) where four U.S. Routes intersect. In addition, there is a level-grade crossing with BNSF Railway tracks very near the intersection, which leads to large amounts of delays.

South of La Grange, U.S. 12/20/45 has a full interchange with Interstate 55 (Stevenson Expressway). It then crosses the Des Plaines River and Chicago Sanitary and Ship Canal before a complex interchange with Illinois Route 171 (Archer Avenue). A ramp from Interstate 294 to U.S. 12/20/45 formerly existed, but was scrapped in the late 1990s due to safety concerns. Just south of the Tri-State Tollway, U.S. 12/20/45 becomes southbound 96th Avenue, passing through Cook County Forest Preserves for nearly two miles before U.S. Routes 12 and 20 split from U.S. 45 onto eastbound 95th Street.

After turning off the U.S. Route 45 routing in Hickory Hills, U.S. Routes 12/20 run east on 95th Street for 16.31 miles (26.24 km) — combined with a concurrency with U.S. Route 41, this segment runs for an additional 18.02 miles (29.00 km) into the state of Indiana.

The 95th Street portion of U.S. 12/20 is a four-lane undivided arterial surface street through the southern suburbs of Palos Hills, Bridgeview, Oak Lawn and Evergreen Park. It serves the main commercial areas of these communities and the Chicago south side neighborhoods of Beverly, Washington Heights, Roseland, Burnside, Pullman, Calumet Heights, South Deering and East Side.

In Bridgeview, U.S. 12/20 has interchanges with Interstate 294 and Illinois Route 43 (Harlem Avenue). In Oak Lawn, it intersects Illinois Route 50 (Cicero Avenue). Further east, in Chicago, U.S. 12/20 nearly intersects Illinois Route 1 (Halsted Street); Illinois 1 technically terminates at Interstate 57 a half mile (.8 km) south. U.S. 12/20 then has an interchange with Interstate 94 (Dan Ryan Expressway) just north of the Interstate 57/94 split. Shortly after bridging the Calumet River, U.S. 12/20 join with U.S. 41.

The concurrent U.S. 12/20/41 combination runs south on Ewing Avenue beneath the Chicago Skyway, narrowing from two northbound and southbound lanes to one northbound and one southbound lane before turning onto Indianapolis Boulevard, a six-lane divided highway. At 104th Street, there is a traffic light for a relocated offramp (from 106th Street) from the Chicago Skyway to Indianapolis Boulevard. The southbound onramp to the Indiana Toll Road is still located at 106th Street.

The Illinois portion of U.S. 12/20/41 terminates literally beneath the I-90 bridge over Indianapolis Boulevard; this is also where the Chicago Skyway becomes the Indiana Toll Road.

In 1928, U.S. Route 12 followed its current route south from Wisconsin into Richmond. It then continued straight on what is now Illinois 31 to Crystal Lake, and then ran along what is now U.S. Route 14 into Chicago. This route began to be depicted on Chicago maps in 1932 along the Northwest Highway, Foster Avenue, Lake Shore Drive, South Parkway (now most likely the 57th Street / Cornell Avenue combination), Stony Island Avenue and 95th Street.

From 1928 to 1929, the section between the Wisconsin state line to Crystal Lake was being constructed; this segment was designated Temporary U.S. Route 12 at the time.

In 1938, U.S. 12 was moved north off of the U.S. 14 routing to the current routing to Des Plaines. In addition, U.S. 12 was moved to what is now Mannheim Road, La Grange Road and 95th Street. The former U.S. 12 became City U.S. Route 12.

In 1939, U.S. 12 was moved to a bypass around Lake Zurich.

There were no further changes to the U.S. 12 routing until 1960, when City U.S. 12 became Business U.S. Route 12. In 1963, U.S. 12 was moved onto the Chicago Skyway and became Toll Business U.S. Route 12 until 1968, when all Business U.S. 12 designations were dropped.

In Illinois, the highway has been designated as the Iron Brigade Memorial Highway to honor the Civil War Union Army unit, a designation it also has in Michigan, Indiana and Wisconsin.

A bypass is currently being planned for U.S. Route 12 around Richmond, IL. The bypass is planned to run from the end of the U.S. 12 Freeway at Genoa City along the FAP 420/FAP 342 corridor and terminate just south of the town, at Illinois Route 31.