Highways that have been superseded by an Interstate, US 12 remains intact as an important link for local and regional destinations.

The eastern section of US 12, through remote mountain forest and up to Lolo Pass, was built in the early 1960s, making it the last U.S. Highway constructed.

US 12 is a two-lane undivided highway that runs 87.47 miles (140.77 km), through Adams, Bowman, and Slope counties in southwest North Dakota.

At Walker, US 12 heads southeast for 37 miles (60 km), where it crosses the Missouri River at Mobridge, exiting the reservation.

After leaving US 83, it turns due east and spends about 80 miles (130 km) as a rural two-lane highway again.

[16][17] US 12 crosses the St. Croix River from Lakeland, Minnesota, into Hudson, running concurrently with I-94 before splitting just east of the city.

It mainly follows a similar path to I-94 to the north, before crossing under I-94 into downtown Menomonie before continuing in an easterly direction through Eau Claire.

It then turns east for 4.5 miles (7.2 km), then parallels I-90/I-94 through Camp Douglas, New Lisbon, Mauston, and Lyndon Station before crossing under the pair of Interstates into downtown Wisconsin Dells.

In Hickory Hills, US 45 continues south, while US 12/US 20 runs due east along 95th Street in the southwest suburbs.

From Hickory Hills, US 12/US 20 runs east nearly to the Lake Michigan lakefront and then joins with US 41, as all three routes travel southeast into the state of Indiana.

Rand is an original name for the area around Des Plaines, the location where the road resumes its westerly direction.

It runs from an interchange with the Indiana Toll Road, concurrent with US 20 and US 41 in Whiting, to Michiana Shores, at the Michigan state line.

US 12 is now the only U.S. Highway still serving Downtown Detroit, whose street grid was laid by Augustus B. Woodward, to have a five-way intersection of the roads that would become US 12, US 10, US 16, US 112 and US 25.

The east–west corridor traverses the counties of Berrien, Cass, St. Joseph, Branch, Hillsdale, Lenawee, Washtenaw, and Wayne.

Since the highway's creation in 1926, the eastern terminus has always remained within a few blocks of Cadillac Square in Downtown Detroit, Michigan.

The 1974 "Golden Anniversary Celebration" reprint of the 1926 Rand McNally Road Atlas shows US 12 following what later became the route of US 10 through Michigan, from Detroit, through Flint, Saginaw, Midland, and Clare on its way to Ludington.

[19] It was also proposed to enter Oregon on the current route of US 730 from east-southeast of Boardman to a point northeast of Cold Springs, but that was canceled.

[19] In the 1960s, a portion of US 12 in Western Washington was moved north to the town of Morton, when Mossyrock Dam was built on the Cowlitz River in Lewis County.