The freeway starts at I-80 near Davenport, Iowa, and ends at I-80 near Colona, Illinois; its eastern part runs concurrent with I-74 to return to I-80.

It continues south for four miles (6.4 km), crossing Duck Creek, toward a diamond interchange with Scott County Road F65 (CR F65), which becomes Locust Street in Davenport.

I-280 joins with I-74 at Quad Cities International Airport; this concurrency continues for 9.4 miles (15.1 km) before terminating at the I-74/I-80 interchange.

In the early 1990s, the state of Illinois suggested, via American Association of State Highway and Transportation Officials (AASHTO) and Intermodal Surface Transportation Efficiency Act (ISTEA) hearings, swapping the I-80 and I-280 designations around the Quad Cities.

One of the reasons Illinois pursued the matter was due to the configuration of the eastern terminus of I-280; as a simple cloverleaf interchange, through I-80 traffic (along the north and east branches) was required to exit on both directions.