It runs north–south in central Wisconsin from West Milwaukee to just south of Fond du Lac.

The northern terminus was moved from US 45 near Oshkosh to its present location near Fond du Lac.

The portion in Winnebago County became County Trunk Highway R (CTH-R), and the portion in Fond du Lac County (including through the Van Dyne, North Fond du Lac, and Fond du Lac communities) became CTH-RP.

Beginning in May 2015, US 41 south of Howard underwent conversion to Interstate 41 (I-41) and rerouted to follow an existing freeway alignment in Milwaukee County.

[4] In 2016, Urban Milwaukee contributor John O'Neill wrote an article suggesting partial removal of the highway in order to improve pedestrian safety.