It runs from the Dale Gardner Veterans Memorial Bridge over the Mississippi River between Sabula, Iowa, and Savanna with Illinois Route 64 (IL 64) southeast to the Indiana state line near Sheldon with US 24.

US 52 travels southeast from the Dale Gardner Veterans Memorial Bridge at the terminus of Iowa Highway 64 (Iowa 64) and IL 64 in Savanna, going through the cities of Dixon, Amboy and Mendota.

US 52 then turns due south and then east, crossing Interstate 39 (I-39) and US 51 near Troy Grove.

It continues east, traveling through Shorewood and then through the southern portion of Joliet, where it is a major thoroughfare in the city of Joliet (Jefferson Street), avoiding the city of Chicago proper.

It joins with US 45 through Kankakee, and then travels concurrently with US 24, east of Watseka to the Indiana state line.