River rising in Lake Shetek* in southwestern Minnesota, U.S., near Pipestone, and flowing 525 mi (845 km) in a southeasterly direction to join the Mississippi River 2 mi southwest of Keokuk, Iowa. Above Humboldt, Iowa, the river is known as the West Fork. The East Fork and the Raccoon River are its principal tributaries. For a distance of 25 miles (40 km) above its mouth, the river serves as the boundary between Iowa and Missouri. Along its course, the river falls 1,375 feet (419 m) and drains an area of 15,807 square miles (40,940 square km).

From the late 1830s until the close of the American Civil War, the Des Moines River was the main artery of commerce for central Iowa. A decline in river traffic came with the development of railroads. The river was early utilized for power, and, although none survive, 80 mills for grinding grain were built along its banks between 1840 and 1890. The Red Rock and Saylorville dams were authorized in 1958 for flood control. Major riparian cities include Ottumwa, Des Moines, Fort Dodge, and Estherville, all in Iowa.

*"Shetek" is a Dakota word meaning "pelican." Lake Shetek is the headwaters of the Des Moines River.  The State Park has 1,109 acres with 8 miles of trails, 108 campsites, beach, playground, boat and canoe rental, and modern group camp. The park is open all year and heavily used during the summer.  Area attractions include the Pipestone National Monument, Jeffers Petroglyphs, Currie Railroad Museum, and Laura Ingalls Museum in Walnut Grove.