US 10 enters the state and Pierce County from Minnesota at Prescott and immediately joins with Wisconsin Highway 35 (WIS 35) north. WIS 35 turns north 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, intersecting with WIS 80. US 10 becomes an expressway at this intersection, and continues as an expressway until the Wood–Clark county line. The highway then passes south of Marshfield, meeting WIS 13 south of Marshfield at a diamond interchange. US 10 then passes south of Auburndale and enters Portage County near Milladore.