It runs from U.S. Route 150 by unincorporated Lynn Center to Illinois Route 78 (Main Street) in Kewanee.

In addition to Kewanee, Illinois 81 also serves Andover and Cambridge.

SBI Route 81 was established as Lynn Center to Kewanee.

The routing of Illinois 81 has not changed since it was established.

The entire route is in Henry County.