The highway often serves as a direct route for travelers between Appleton and Oshkosh to Tomah and La Crosse.

The highway then turns eastward and follows alongside the Tarr and Sparta creeks, passing through Tunnel City.

The highway continues east from there to junction with WIS 173 west of Wyeville and then crosses into Juneau County.

[7] WIS 21 continues along Omro Road, Oshkosh Avenue and Congress Avenue, ending at US 45 (Algoma Boulevard) on the northwest side of Oshkosh after crossing the upper Fox River east of Lake Butte des Morts.

[9] The highway passed through Sparta, but through the south side of Tomah and New Lisbon before turning north to Necedah.

WIS 21 then returned to the present corridor route to pass through Coloma, Wautoma, Omro and into Oshkosh.

[10] The route from La Crosse to New Lisbon was removed in the early 1920s and extended along its current alignment through Wyeville to North Tomah.