It arises in two forks. The source of the West Fork is Lake Shetek in southwestern Minnesota in Murray County. The source of the East Fork is Okamanpeedan Lake on the border between Minnesota and Iowa.

The two forks join in Humboldt County, Iowa and proceed roughly southward through Iowa, passing through the city of Fort Dodge and Des Moines before turning southeastward, after which it flows through the city of Ottumwa (where it becomes navigable) and empties into Mississippi near the town of Keokuk.

Along the last thirty miles of its length, it forms part of the boundary between Iowa and Missouri.

Near the town of Boone is central Iowa, it formed a group of rocky gorges called the Ledges.

Above the city of Des Moines, it is dammed to create the reservoir Saylorville Lake. Above Ottumwa, it is dammed to create the reservoir Red Rock Lake.