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The river begins about 15 miles (24 km) north of McClusky, North Dakota, and flows generally eastward before turning south near McVille. The southerly flow of the river continues through Griggs and Barnes counties before it turns in a northeastward direction near Lisbon. The river forms Lake Ashtabula behind the Baldhill Dam north of Valley City.
From Lisbon, the river crosses the Sheyenne National Grassland and enters Cass County near the city of Kindred. From Kindred, the river flows north-northeastward through the fertile plains of the Red River Valley.
The character of the river changes as it leaves the sandy grasslands and picks up the fertile clay soil of the Red River Valley. Previously, the river posed a flooding hazard to cities such as West Fargo and Harwood, where it joins the Red River of the North and flows north to Lake Winnipeg in Manitoba. Thanks to a diversion canal completed near Horace, the major Sheyenne River cities fared well in the 1997 Red River Flood which devastated the cities of Grand Forks, North Dakota and East Grand Forks, Minnesota.
It is crossed by several historic bridges, including the Lisbon Bridge and the Colton's Crossing Bridge in Lisbon, the West Park Bridge in Valley City, the West Antelope Bridge in Flora, the Romness Bridge near Cooperstown, the Westgaard Bridge near Voltaire, and the Nesheim Bridge at McVille.
- U.S. Geological Survey. National Hydrography Dataset high-resolution flowline data. The National Map, accessed June 8, 2011
- Upham, Warren (1920). Minnesota Geographic Names: Their Origin and Historic Significance. Minnesota Historical Society. p. 119.
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