U.S. Highway 10 (US 10) in Wisconsin runs east–west across the central part of the state. It runs from the Prescott Drawbridge over the St. Croix River at Prescott east to the dock in Manitowoc where the SS Badger crosses Lake Michigan to Ludington, Michigan.

U.S. Highway 10 enters the state and Pierce County from Minnesota at Prescott and immediately joins with WIS 35 north. WIS 35 turns north 1-mile (1.6 km) northeast at WIS 29 while US 10 continues east and passes through Ellsworth at the junctions with WIS 65 and US 63 The highway turns southeast and passes through Ono and Plum City. US 10 then enters Pepin County and junctions with WIS 25 and WIS 85 at Durand US 10 briefly enters Buffalo County and passes through Mondovi at the junction with WIS 37. In northern Trempealeau County, the highway crosses WIS 93 at Eleva, passes through Strum, and junctions with US 53 and I-94 in Osseo. The route then enters Jackson County where it joins US 12 and WIS 27. US 12 and WIS 27 split to the south at the Clark County line while US 10 continues east to Neillsville and crosses WIS 73 there. The highway then meanders northeast into Wood County, passing south of Marshfield and crossing WIS 13. US 10 then passes through the community of Auburndale and enters Portage County at Milladore.

US 10 meets WIS 34 north at two miles (3 km) west of Junction City. WIS 34 splits north two miles (3 km) east of Junction City while US 10 turns east and bypasses Stevens Point on a new freeway. In Stevens Point, the old US 10 has been replaced by WIS 66 which travels through downtown and near the University of Wisconsin–Stevens Point just east of downtown. The highway then meets I-39 / US 51 north of the city and runs concurrent with I-39 / US 51 for about seven miles before exiting to the east of Stevens Point. At this point, US 10 becomes a multilane expressway and heads southeast, passing through Amherst and crossing into Waupaca County. US 10 bypasses the city of Waupaca to the south and junctions with WIS 22, WIS 54 and meets WIS 49 south. US 10 and WIS 49 turn eastward to Weyauwega then head south to Fremont where WIS 49 turns south and US 10 becomes a freeway at the junction with WIS 110. US 10 collects US 45 south in northwest Winnebago County for a three mile (5 km) southeast trek before US 45 splits to the south and US 10 turns east to rendezvous with WIS 441 at the junction with US 41 in Neenah. US 10 turns south off the WIS 441 freeway south of Appleton and turns east into Calumet County.

As a multilane urban arterial, US 10 collects WIS 114 for four miles (6 km) before the latter splits south two miles (3 km) before US 10 junctions with WIS 55. The highway then crosses WIS 32 and WIS 57 at Forest Junction and turns southeast to pass through Brillion and into Manitowoc County. The highway passes through Reedsville and Whitelaw before turning south onto I-43 for three miles (5 km) and turning east off the Interstate to head along WIS 42 into the north side of Manitowoc. US 10 then turns south into downtown where it continues into Michigan via the S.S. Badger carferry to Ludington.

Prior to 1926, what is now US 10 was State Trunk Highway 18. However, Highway 18 initially (in 1917) only ran from Humbird, near where US 10 and U.S. Highway 12 (then State Trunk Highway 12) cross, east to Manitowoc. State Trunk Highway 34 ran from Prescott to Highway 37 in Mondovi. The route between Mondovi and Humbird was not numbered until the early 1920s, when Highway 18 was extended west from Humbird past Mondovi to Prescott, eliminating Highway 34.

When US 10 was designated in late 1926, it ran along U.S. Highway 12 from Minnesota east to Humbird, splitting there to run to Manitowoc. The piece of former Highway 18 west of Humbird became Highway 34, as the number 18 conflicted with U.S. Highway 18. In 1934, Highway 34 disappeared again, as US 10 was separated from the US 12 concurrency to run along it.

WisDOT is in the process of relocating US 10 out of Stevens Point by joining it with I-39 north to the CTH-X interchange. A US 10 expressway will then turn west, bypassing smaller communities and end at WIS 13 south of Marshfield. Construction began in 2007 and will finish in 2012. This project will complete US 10 as four-lane facility from Marshfield to Menasha, a project started in the late 1990s. The only segment of the highway not a divided expressway will be from I-39 in Stevens Point to CTH-J.