It runs north–south in southwest and west central Wisconsin from just south of Marshfield, near the geographic center of the state to the Illinois border near Hazel Green.

As WIS 80 leaves Platteville it heads north along the Iowa-Grant county line past Livingston and into Montfort.

North of Muscoda, the highway passes through Richland Center and Hub City before entering Hillsboro and joins with WIS 33/WIS 82.

The three-way concurrency leaves Hillsboro and enters Union Center, where WIS 33 leaves the concurrency and WIS 80/WIS 82 go north to the southern trailhead of the Elroy-Sparta State Trail, the northern trailhead of the 400 State Trail, and Elroy.

South of Hazel Green, WIS 80 ends at the Illinois state line, where it meets Illinois Route 84 (IL 84) one-half mile (0.80 km) west of the state's "Point of Beginning",[1] the location from which most public land surveys in Wisconsin originated.