The highway connects the cities of Minot and Fargo and travels concurrent with Interstate 94 (I-94) between Jamestown and the Minnesota state line.

US 52 passes through Burke, Ward, Renville, McHenry, Pierce, Sheridan, Wells, Foster, Stutsman, Barnes, and Cass counties.

From a point halfway between Foxholm and Burlington, and the southeast edge of Minot, US 52 is co-signed with US 2.

Further south, US 52 is also co-signed with US 281 for 44 miles (71 km) between Carrington and Jamestown.

From Jamestown east to the Minnesota border at Fargo, the highway is co-signed with Interstate 94.