In the U.S. state of Wisconsin, U.S. Route 45 (normally called U.S. Highway 45, Highway 45 or US 45) runs north–south through the eastern and northern portions of the state.

US 45 enters from Illinois at Pikeville and is a two-lane road up to its junction with WIS 36 southwest of Milwaukee. It runs concurrent with WIS 36 to its junction with WIS 100. As it follows WIS 100 north, it becomes an Urban multilane road. It merges onto Interstate 43 north in Greenfield then follows I-894 north from the Hale Interchange one mile (1.6 km) to the east. After I-894 ends at I-94, US 45 continues as a freeway north into Wauwatosa where it merges with US 41. The two routes split further north with US 45 continuing to West Bend. The freeway section of US 45 ends north of West Bend.

US 45 parallels US 41 as a two-lane rural road and passes through Fond du Lac, and Oshkosh, then turns northwest as a freeway facility to US 10 in Winchester. 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. The route leaves the state at Land O' Lakes.