On its western end, the highway is mostly a two-lane road that runs through the southern tier of counties roughly parallel to the Indiana state line.

In between Coldwater and the Ann Arbor area, the highway angles northeasterly and passes Michigan International Speedway.

Between the state line near Michiana and the interchange with I-94 near New Buffalo, US 12 forms a portion of the Lake Michigan Circle Tour (LMCT).

The trunkline continues northeasterly through northern Hillsdale County, crossing the South Branch of the Kalamazoo River in Moscow.

East of the racetrack, the highway meanders through an area dotted by several smaller lakes until it intersects M-124 at Hayes State Park.

[4][7] Once US 12 intersects the eastern end of its business loop, it returns to Michigan Avenue for the remainder of its routing in the state.

[8] US 12 continues through residential areas on Detroit's West Side, passing through the interchange that connects I-75 with I-96's eastern terminus near the Ambassador Bridge.

[14] The wide width of the avenues was an emulation of the street plan for Washington DC and intended to make Detroit the "Paris of the West".

Father Gabriel Richard, the first priest to serve in the U.S. House of Representatives, petitioned Congress to fund a highway between Detroit and Chicago in March 1824.

Another new segment of highway opened that same year east of Jackson, bypassing Leoni and Grass Lake to the north.

[36][37] The last routing change in the 1930s was the opening of Stadium Drive in Kalamazoo, after which US 12 was rerouted to follow it west of downtown.

[40][41] In late 1951 or early 1952, a northerly bypass of Jackson opened, and the former route through downtown on Michigan Avenue became another Bus.

[44][45] In 1954, a new bypass of Kalamazoo and Galesburg opened; US 12 was rerouted to follow the new highway while M-96 replaced part of the old route and the US 12A in the area.

[50][51] Previously delayed so that the designations could be finalized,[52] the MSHD started numbering its Interstate Highways in 1959, adding I-94 to the sections of US 12 freeway.

[57] In January 1962, the state made the biggest rerouting change of all to US 12: the designation was removed from the I-94 freeway from New Buffalo to Detroit and shifted to completely replace US 112.

[71][72] In October 2000, the state proposed changing jurisdiction of several highways near Campus Martius Park in Detroit,[73] and US 12 was shortened by four city blocks the next year to end along Michigan Avenue at Griswold Street.

[76][77] In April 2017, MDOT announced the reconstruction of US 12 east of Ypsilanti, which would reduce the route from a boulevard to a singular road along the existing eastbound lanes.

This project would also eliminate an interchange with Wiard Road and allow the adjacent American Center for Mobility to use the westbound lanes as part of a facility to test automated vehicles.

It was already labeled the Michigan–Detroit–Chicago Highway on travel maps of the time, so the paper suggested that the roadway should be renamed to create the longest street in the country.

Albion was the first community to change the name of its street followed by Jackson and Marshall in 1924, Battle Creek in 1928, and Kalamazoo in 1929.

Jurisdiction of most of the roadways that composed US 12 at that time has passed to local governments as I-94 was built, but the highway still bears that name in Berrien[80] and Van Buren counties.

[81] Count Casimir Pulaski was a Polish-born noble and soldier who fought on the side of the Americans during the Revolutionary War.

The route of US 112 was designated the Pulaski Memorial Highway by Public Act 11 of 1953 and formally dedicated in Detroit on October 4, 1953.

[85] The name honors the 24th Michigan Infantry Regiment, part of the Iron Brigade from the American Civil War.

The regiment lost more troops than any other on the Union side during the war and provided the military escort for Abraham Lincoln's funeral in Springfield, Illinois.

The highway was dedicated in twin ceremonies in New Buffalo on October 9, 1994, and in Detroit on November 11, 1995, to the Iron Brigade.

From there, the business loop followed Chicago Road northeasterly through residential areas on the west side of town.

The loop intersected the southern end of M-139 at Front Street one block east of the river in downtown Niles.

US 12 designation was retired when an extended M-139 replaced it from the local control section southwestward prior to maps and signage being changed.

Michigan Avenue crosses the Huron River and continues due east until an intersection at Prospect Street where it turns northeasterly.