The highway runs north-northwesterly from an interchange with Interstate 43 (I-43) in Bellevue, Wisconsin, near Green Bay, to a junction with US 41/M-28 near Covington, Michigan.

North of Green Bay, US 141 is either a freeway or an expressway into rural northern Wisconsin before downgrading to an undivided highway.

[4] From the Green Bay suburb of Howard northward, including the entire length through Michigan, US 141 is a part of the NHS.

[8][9] From Howard northward, the freeway runs through suburban Brown County to Suamico, parallel to a line of the Escanaba and Lake Superior Railroad (ELS), through a mixture of farm fields and residential subdivisions.

The landscape north of the split transitions to forest, and the freeway crosses the Oconto River in Stiles south of the interchange with WIS 22.

It crosses a railroad track at the surface and continues north through mixed farm fields and forest to the county line.

The highway crosses a branch line of the ELS on the east side of Crivitz and continues north through woodland to the community of Middle Inlet.

The highway then turns north along Roosevelt Road and over the Menominee River to exit the state of Wisconsin.

The two highways run concurrently westward into Iron Mountain along Stephenson Avenue, passing through a retail business corridor and into downtown.

[8][10] US 2/US 141 makes a 14.5-mile (23.3 km) run through Florence County, passing the Spread Eagle Chain of Lakes.

The highway crosses back into Michigan on a bridge over the Brule River south of Crystal Falls.

[7][8] Across the state line, the trunkline runs through forest near several smaller bodies of water such as Stager, Kennedy, and Railroad lakes.

Running north and northwesterly, US 141 passes to the east of the Ottawa National Forest through rural Iron County.

[13] The segment through Florence County, Wisconsin, was WIS 69,[11] and from the Crystal Falls area north to Covington, the M-69 moniker was used.

[17][18] By 1924, maps showed an unnumbered roadway running south from Quinnesec to connect with WIS 57 at the state line.

In the original plan, US 102 was supposed to replace M-15 from US 2 at Rapid River, continue via Marquette to Humboldt, and the highway between Crystal Falls and Covington was not included in the system.

[24] The next year, the M-57 designation was assigned to connect WIS 57 to Quinnesec, and US 8 was extended to follow US 141 to US 2 near Iron Mountain.

[25] On November 12, 1928, the extension of US 141 northward from Green Bay along WIS 57 to the Michigan state line had been approved;[21] the signage was readied for installation the previous month.

[39][40] At about the same time as the realignments in Michigan, two-lane bypasses of Manitowoc and Port Washington in Wisconsin were opened in 1957.

[41][42] The state built a divided-highway segment that opened the following year running from the Milwaukee area northward to the Ozaukee–Milwaukee county line.

[43][44] In late 1961, the highway in Michigan was rebuilt in northern Iron and southern Baraga counties between Amasa and Covington as the state smoothed out sharp corners in the routing and finished paving US 141;[45][46] a similar project was completed in 1972 south of Amasa to Crystal Falls.

[49] The first segments of freeway were opened in the Milwaukee area, starting in 1963 between Locust Street and Good Hope Road.

[51][52] By 1965, the bypass of Sheboygan was opened;[49] the Milwaukee area freeway was extended northward to Brown Deer Road the following year.

[55][56] The last section of US 141 in the city of Milwaukee to open as a freeway was completed in 1968 when I-94 was finished through downtown; at the same time, US 141 was extended southward from North Avenue to meet I-94.

[59][60] In 1972, the divided-highway segment between Suamico and Abrams opened,[60][61] and the state started the construction of additional freeways between Green Bay and Milwaukee.

[73][74] On April 7, 2015, the segment of US 141 that runs concurrently with US 41 on the west side of Green Bay was designated a part of I-41 by the Federal Highway Administration.

[78] In 2006, the US 141 expressway was extended northward near Beaver, and the former route of US 141, plus a connector roadway southwest of downtown Coleman was designated as a business loop.