In the US state of Wisconsin, U.S. Highway 41 (Highway 41, US-41) runs north–south the eastern side of the state. It enters from Illinois (concurrently with I-94) at Pleasant Prairie, and runs north to its northern terminus at the Michigan border at Marinette, WI.

US-41 is a freeway for nearly 70% of its route through Wisconsin, with the exceptions being a stretch in Milwaukee (Lisbon and Appleton avenues) and an expressway section north of Green Bay. South of Milwaukee, the route is concurrent with I-94 all the way to the Illinois border.

US-41 leaves Milwaukee to the northwest and passes Fond du Lac, Oshkosh, and Appleton before heading to Green Bay. The route is a major access point for Miller Park, home of the Milwaukee Brewers Major League Baseball club, the EAA AirVenture Oshkosh air show in Oshkosh, and for Lambeau Field, the home of the Green Bay Packers NFL football team.

After leaving Green Bay, US 41 continues north to Abrams co-signed with US 141, and then it turns east off the co-signed route toward Marinette and into Michigan.

In Milwaukee the original routing of US 41 used Lisbon Avenue east to North 27th Street, then south along that road to the Illinois state line. After the Stadium Freeway was built in the 1960s, US 41 followed that road from Lisbon Avenue south across I-94 to National Avenue and then east to 27th Street, which is known as Layton Boulevard between National Avenue and Lincoln Avenue. WisDOT rerouted US 41 along I-94 from the Stadium Interchange to the Illinois state line, removed Layton Boulevard north of Forest Home Avenue from the state highway system and gave Layton Boulevard and 27th Street south of Forest Home Avenue the designation of WIS 241 in a compromise to avoid expansion of the original route. The old US 41 freeway section south of I-94 to National Avenue (which was realigned to accommodate the construction of Miller Park) was designated WIS 341 but is unsigned. Trailblazer signs indicate it as Miller Park Way.

By 1955, US 41 was relocated from the corridor of today's WIS 175 and its successors to a nearby expressway in Winnebago, Fond du Lac, Dodge, Washington, Waukesha, and Milwaukee Counties.

In Green Bay, the road used to make a curve to the right west of De Pere, going onto Ashland Avenue to the Green Bay city limits. It then turned left onto Highland Avenue (after 1968, Lombardi Avenue), going past Lambeau Field and curving right onto Military Avenue. It then turned left at Velp Avenue. At the time, this was the outer highway for Green Bay, and the site for Lambeau Field was chosen because of highway access. The area now is urbanized. It then followed present day Velp Avenue north to Suamico where it merged with what is now the US 41 freeway. The original Green Bay bypass was once again bypassed with the present US 41 freeway beginning at Velp, southerly to Lombardi in 1968; Velp north to Suamico in 1971; then from Lombardi south to De Pere in 1974.

Appleton also saw its fair share of US 41 realignments over the course of time, beginning with the 1937 two-lane bypass (along the present freeway route) from Neenah northerly to a T-intersection with US 10 (today's Wisconsin Avenue, WIS 96). There, US 41 turned east with US 10, back to its original route at the intersection of US 10 (Wisconsin Avenue) and Richmond Street north of downtown Appleton, then north on Richmond to present day Northland Avenue. There it turned east on new alignment back to the original route northeast of Kaukauna. In 1940, US 41 was extended northerly from the T-intersection at US 10 for one mile (1.6 km), before making a large sweeping curve onto present day Northland Avenue to join back up with the previous bypass at Richmond Street. By 1962, the original Appleton bypass had been converted to four-lane divided highway from Oshkosh north to Northland Avenue, then north and east on new alignment bypassing the Northland Avenue bypass with the current freeway easterly to Kaukauna.

US 41 is either undergoing major construction, or in the planning stages for future construction, between Milwaukee and Green Bay to upgrade it to Interstate standards. Currently, interchange upgrades are also underway on US 41 near Fond du Lac, Oshkosh and Green Bay. Between now and 2015, US 41 will undergo capacity upgrades through the Oshkosh and Green Bay areas, converting the existing four-lane freeway to a six-lane freeway in both cities. US 41 has also been upgraded to 4-lane expressway between Oconto and Peshtigo, which includes freeway bypasses of both cities. The Oconto-to-Peshtigo stretch had been the final two-lane segment of US 41 in the state, and opened as a four-lane expressway between the two cities as of November 2008. The Oconto and Peshtigo bypasses were completed November 19, 2009. At present, US 41 is constructed to freeway standards from the north side of Milwaukee, all the way north to the US 41/141 interchange in south-central Oconto County, approximately 19 miles (31 km) north of Green Bay.

Wisconsin Department of Transportation (WisDOT) officials are studying what improvements need to be made to U.S. Route 41 in order for it to be upgraded to Interstate status. Necessary upgrades must be made before any signage changes can happen, but the 142 miles (229 km) route from Milwaukee to Green Bay is expected to be designated as a new interstate Highway by 2014, initially proposed as Interstate 41. The legislation was added to the 2005 federal highway bill (Transportation Equity Act: A Legacy for Users) by Congressman Tom Petri. Gannett Wisconsin newspapers reviewed the state traffic records, and found that the number of cars traveling on 41 in northeast Wisconsin has nearly doubled since 1994. Some officials in the state feel that designating US 41 as an interstate would bring additional attention and revenue to the area. It is unknown if the US 41 shields will remain when new interstate signs are posted after the reconstruction is complete.

In 2009, Green Bay, Wisconsin officials began a campaign to have US 41 designated as a northern extension of Interstate 55 from its current termination in Chicago, with the alternative being the road as a spur of I-43.

At their spring meeting on May 18, 2012, the Special Committee on U.S. Route Numbers of the American Association of State Highway and Transportation Officials discussed the highway number to be used. The committee discussed the importance of an I-55 number, and will coordinate with the Federal Highway Administration and the Illinois Department of Transportation on the usage of that number.

On October 17, 2012, WisDOT officials revealed they recommended to the American Association of State Highway and Transportation Officials that they wanted to have it designated I-41. If that is turned down, it was suggested to be designated I-47, I-594, or I-643. WisDOT did not forward suggestions for I-55 or I-57 extensions from northern Illinois as was previously rumored. In mid-November 2012, AASHTO tentatively approved—pending approval from FHWA—the I-41 designation along US 41 from the Illinois state line to I-43 in Green Bay.

Two expansion projects are scheduled. The first upgrades the old rural freeway west of Green Bay from CTH F (Scheuring Rd) past I-43 to CTH M (Lineville Rd) to a six-lane road with the rebuilding of all interchanges along the corridor; including a free-flow interchange with WIS 29. The second is an expansion of the highway from WIS 26 to Breezewood Lane around Oshkosh from 4 to 6 lanes – including rebuilding 9 interchanges and the Lake Butte des Morts causeway. The bridge over Lake Butte des Morts is scheduled to be expanded to eight lanes. The second plan has a $292 million budget, and is scheduled to include two additional park and ride lots at State Highways 26 and 76. As of May 2011, the upgrades to interstate level are anticipated to be completed by 2015 and cost between $15 – 20 million.

Studies are also underway on upgrading the US 41/US 10/WIS 441 interchange in the Neenah area. Currently, the interchange is missing the US 10 Eastbound to US 41 Northbound, and US 41 Northbound to US 10 Westbound ramp movements. This study is focusing on ways to reconstruct this interchange to allow all ramp movements.