As from the earliest days of its existence, US 12 enters Michigan from Indiana, southwest of and continues to the old junction of US 12 and US 112 in New Buffalo. It is now assigned between New Buffalo and Detroit (except through Ypsilanti), along what was US 112 until 1962.
US 12 is now the only U.S. highway route still serving downtown Detroit, whose was laid by , to have a five-way intersection of the roads that would become US 12, , , and . still travels through Detroit from Puritan to on the far west side.
The western terminus of US 12 is located in . In the 1960s, a portion of US 12 was moved north to the town of , when the was built and flooded the towns of and Riffe, along the in . A large portion of old, two-lane US 12 was replaced by and in the 1980s, between and the , though the freeways are still cosigned with the US 12 designation. The old two-lane highway now bears the name . The highway loosely follows the eastbound leg of the , between and , thus being marked as part of the . The east end of the highway in the state is at , where the highway crosses the into at .
US 12 enters the state at , crossing the from . It ascends the , with for 7 miles (11 km) . It reduces to a two-lane undivided highway with signs that read "winding road next 99 miles" and goes on to , continuing up the middle fork of that river to , the junction of the and . It continues up the Lochsa and climbs to at the border. This portion of the highway is also designated as part of the . Most of the highway in Idaho is within the . The eastern section of US 12, through remote mountain forest and up to Lolo Pass, was built in the early 1960s, making US 12 the last constructed. No services are available between Lowell and Powell, about 70 miles (110 km) further east. U.S. Route 12 through Idaho has been proposed as a route for shipment of huge equipment from Lewiston, an inland port, to oil sands facilities near and to a refinery in . On two-lane portions of the road, the equipment, weighing as much as 300 tons and as much as 30 feet high and 24 feet wide, would occupy the entire roadway. The route is preferable to other routes due to the lack of underpasses and the great distances involved. The alternative is transport across the Great Plains from or On U.S. 12, the major obstacle would be power lines which would have to be raised or buried. That and other alterations to the highway such as turnouts would be paid for by the companies. The trucks would transport only at night, moving short distances between places where they would pull off and let traffic pass. A permit granted by the to in August 2010 is the subject of litigation initiated by householders along the route. On January 19, 2011 it was announced that the Idaho government would issue permits for four loads of refinery equipment to be transported from Lewiston to Billings.