The freeway section of US 45 ends north of West Bend and continues into Kewaskum as a four-lane highway.

North of Kewaskum, it passes through Waucousta and Eden as it approaches Fond du Lac US 45 reaches a point just south of Fond du Lac, where it joins US 151 and, in a brief wrong-way concurrency, jogs to the west, where it joins I-41.

It then follows I-41 north around Fond du Lac to the junction with WIS 23, and jogs back east, into the center of Fond du Lac, where it then turns north, and follows the shore of Lake Winnebago as a two-lane road, to Oshkosh.

After briefly joining US 10, US 45 takes a northward track as a two-lane rural road and heads into North Central Wisconsin with the exception of a four-lane expressway between Clintonville and Marion.

The route serves as the central street for Antigo and Eagle River and passes into various state and national forest land.