U.S. Route 281 (US 281) is a part of the U.S. Highway System that travels from Hidalgo, Texas and Brownsville, Texas, to its northern terminus at the International Peace Garden, north of Dunseith, North Dakota.

Ten miles north of Sheyenne the highway curves in order to go around Devil's Lake, and then continues to west of Minnewaukan.

The northernmost section of US 281 passes through North Dakota's Turtle Mountains.

US 281 was extended north to the Canada–United States border between 1939[3] and 1940,[4] replacing the remainder of Highway 4.

US 281 was rebuilt near Minnewaukan, North Dakota to accommodate flooding close to the city.