The highway serves as major connecting route between Madison and the southwest corner of the state.

US 18 enters Crawford County from Iowa, crossing the Mississippi River using the Marquette–Joliet Bridge just west of Prairie du Chien.

US 18 and US 61 junction in downtown Fennimore, and WIS 80 north joins the highway in Montfort, on the Iowa County line.

Highways share a common expressway and bypass Ridgeway and Barneveld on the way east into Dane County.

Four miles (6.4 km) east of the Interstates, US 12/US 18 becomes a two-lane surface road again and passes through Cambridge, where US 12 splits southeast at the Jefferson County line.

US 18 turns south from Summit Avenue on the new section of Les Paul Parkway (also known as the new Waukesha West Bypass) and goes the entire route of Les Paul Parkway going around the west, south, and east areas of the city of Waukesha along with the current WIS 59 and WIS 164 configuration from County Trunk Highway X (CTH X), and US 18 joins back up at Moreland Boulevard at the northeast terminus at the Les Paul Parkway/Wolf Road intersection.

[8] US 18 continues through Brookfield and Elm Grove along Blue Mound Road and enters Milwaukee County and Wauwatosa.

[1][13] The eastern terminus was an originally stated in official Wisconsin Department of Transportation documentation to be the junction of East Michigan Street and North Harbor Drive.

That same year, two new interchanges opened in Fitchburg, replacing at-grade intersections with McKee Road (CTH PD) and Williamsburg Way.