It enters from Illinois at Beloit, and runs north to its northern terminus in Hurley at a roundabout junction with US 2.

US 51 enters Wisconsin in Beloit on Broad Street as a four-lane divided highway but immediately merges into a two-lane urban road.

US 51 passes under the railroad and temporarily becomes a four-lane divided highway as it parallels the Rock River again.

US 51 passes Madison Area Technical College and Dane County Regional Airport before going under the Interstate.

Along the way, the route bypasses the small communities of Endeavor, Packwaukee, Westfield, Coloma, Hancock, Plainfield, Plover, and Whiting prior to arriving at Stevens Point.

[2] Proceeding north from Stevens Point, the highway bypasses Knowlton, Mosinee, and Rothschild where I-39 terminates at the WIS 29 east interchange.

[2] Just after the US 8 exit, at the Oneida County line, the freeway ends again and merges into a two-lane rural road.

[2] For much of this stretch the highway runs parallel to the old Milwaukee Road right-of-way, now the Bear Skin State Trail.

North of Woodruff, the highway turns northwest and passes through Manitowish Waters, and Mercer.

Just after Hurley, US 51 ends at a roundabout with US 2 just a couple hundred feet west of the Michigan border.

[3] In 2009 the grade intersection of Star Drive north of Merrill was removed, shortening the 11-mile expressway to nine miles.