The Manitowoc River is formed in eastern Calumet County by its north and south branches:
The South Branch Manitowoc River, the longer of the two at 36.6 miles (58.9 km), rises in northeastern Fond du Lac County and flows generally northeastwardly into Calumet County, passing the city of Chilton and collecting the Killsnake River.
The North Branch Manitowoc River rises in northern Calumet County and flows 22.2 miles (35.7 km) generally southeastwardly.
From the confluence of its forks, the Manitowoc flows generally eastwardly through central Manitowoc County to its mouth at Lake Michigan in the city of Manitowoc. Its largest tributary is the Branch River.