US 85 enters North Dakota in the southwest part of the state. The first city on its route is Bowman at the junction of US 12. Continuing north, it passes between North Dakota's two highest points, White Butte and Black Butte. Near Amidon US 85 heads east for nine miles (14 km) before going back north along the Little Missouri National Grassland for about 125 miles (201 km). Near Belfield it junctions with Interstate 94 (I-94). After running concurrently with North Dakota Highway 200 (ND 200), it eventually passes through part of the scenic Badlands, crosses the Little Missouri River and passes near the Theodore Roosevelt National Park (North Unit).

Then, at Watford City it travels west for 16 miles (26 km) where it turns back north before Alexander. US 85 continues north as ND 200 turns west toward Montana. South of Williston it crosses the Missouri River. The stretch from Watford City to Williston is in the process of being converted into an undivided four-lane highway, and it should be substantially completed in 2014.^{[needs update]} A few miles later, it meets with US 2 where the two overlap for 19 miles (31 km) as an expressway that bypasses Williston to the northwest. After US 2 heads east, US 85 continues north to a concurrency with ND 5. From there it is seven miles (11 km) to Fortuna where US 85 heads back north for its remaining six miles (9.7 km) to the Canadian border.^[1]