Starting in the early 1960s, segments of I-75 and I-94 were built, and US 25 was shifted to follow them south of Detroit to Port Huron.

A business loop was created when the main highway bypassed downtown Port Huron, and then in 1973, the entire designation was removed from the state.

[4][5] The highway followed Telegraph Road through downtown Flat Rock and continued into the suburban area of Downriver.

At the intersection with Dix–Toledo Road near Woodhaven, US 25 separated from US 24 and continued northeasterly for about two miles (3.2 km) to an interchange with I-75 where it merged onto the freeway.

The freeway curved to run east-northeasterly and passed through an industrial area of the city, crossing the River Rouge.

At Clark Avenue, US 25 left the freeway to turn a block south and run along Fort Street parallel to I-75.

Gratiot Avenue carried the highway through residential neighborhoods and connected it to the Detroit City Airport.

At Hall Road near Selfridge Air National Guard Base, M-59 merged with US 25 to follow Gratiot Avenue.

[5][6] I-94/US 25 ran northeasterly through rural areas of Macomb County, intersecting the southern end of M-19 near New Haven.

South of Lakeport, the highway changed names to Lakeshore Road and ran along the Lake Huron shoreline in The Thumb region of the state.

North of the park, the highway crossed into southern Sanilac County and followed the shoreline to the community of Lexington where it intersected the eastern end of M-90.

On the other side of the county line, the highway passed through the community of White Rock and continued along the lake to Harbor Beach.

There, US 25 intersected the eastern end of M-142 and began to curve around to the northwest to follow the northern tip of The Thumb.

About 8 miles (13 km) north of Harbor Beach, the highway passed through Port Hope and turned even more to the northwest on Lakeshore Road.

The highway was further inland on this east–west segment as it ran south of Pointe Aux Barques to Port Austin.

At an intersection with M-53 (Van Dyke Road), US 25 merged with M-53 to run five blocks north along Lake Street to the waterfront in Port Austin.

[10] In 1915, the Dixie Highway, an auto trail that ran south to Miami, Florida, was extended northward to Detroit,[10] and further in 1919 to the Straits of Mackinac.

[27] The second in Port Huron provided access to the Blue Water Bridge from the mainline of the highway starting in 1940.

[37] The southern section from the state line northward through Monroe was renumbered M-125 and the US 25 designation was removed from US 24 (Telegraph Road).

[38] US Highway 25A (US 25A) was an alternate route near Port Huron that provided a connection to the Blue Water Bridge to Canada.

It then passed through the city's downtown area and turned northward along Gratiot Boulevard near the St. Clair River.

US 25 split into the one-way pairing of Military Street (northbound) and Electric Avenue (southbound) until the two directions merged on the south side of Port Huron.

The business loop continued northward along through downtown Port Huron and across the Black River near its mouth.

In the process, that highway replaced its alternate route, and the former alignment through downtown was redesignated as a business loop.