Illinois 251 terminates about 8 mi (13 km) north of the southern terminus of I-39.

The road parallels the east bank of the Rock River through Rockford, where the highway goes north on Eleventh Street, west on Harrison, north on Kishwaukee, west on Walnut then split between northbound Third and southbound Second through downtown Rockford.

After downtown, both directions take the southbound lanes' Second Street name as a divided urban expressway (also badged as Martin Luther King Jr. Memorial Drive) for a couple of miles north of downtown Rockford.

It stays Second Street through Loves Park, Machesney Park and Roscoe until its north endpoint at US 51 and Illinois 75 in South Beloit, .25 miles (0.40 km) short of the Wisconsin state line.

Illinois 251 was established in 1982 when first segment of I-39 opened between Rockford and Bloomington.