The Des Moines River is a tributary of the Mississippi River, approximately 525 miles (845 km) long to its farther headwaters, in the upper Midwestern United States. The largest river flowing across the state of Iowa, it rises in southern Minnesota, and flows across Iowa from northwest to southeast, passing from the glaciated plains into the unglaciated hills near the city of Des Moines, which takes its name from the river. It forms a short portion of Iowa's border with Missouri in Lee County. The Avenue of the Saints passes over this section.

The Des Moines River rises in two forks. The West Fork (the main branch) rises out of Lake Shetek in Murray County in southwestern Minnesota. It flows south-southeast into Emmet County, Iowa, past Estherville. The East Fork rises out of Okamanpeedan Lake in northern Emmet County on the Iowa-Minnesota border and flows south, through Algona.

The two forks join in southern Humboldt County, approximately 5 miles (8 km) south of Humboldt at Frank Gotch State Park. The combined stream flows roughly southward through Fort Dodge. South of Boone it passes through the Ledges State Park. It flows through downtown Des Moines, then turns generally southeastward, flowing through Ottumwa. It forms approximately 20 miles (32 km) of the border between Iowa and Missouri before joining the Mississippi from the northwest at Keokuk.

It receives the Boone River from the northeast approximately 20 miles (32 km) southwest of Fort Dodge. It receives the Raccoon River from the west in Des Moines. Above the city of Des Moines, it is impounded to create the Saylorville Lake reservoir. About midway below Saylorville and above Ottumwa, near Pella, it is impounded to create the Lake Red Rock reservoir.

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