U.S. Route 10 is an east–west United States highway formed in 1926. Though it never became the cross-country highway suggested by the "0" as the last digit of its route number, U.S. Highway 10 was one of the original long-haul highways, running from Detroit, Michigan, to Seattle, Washington, but then losing much of its length when new Interstate Highways were built on top of its right-of-way. In 2010, its length is 565 miles (909 km).

U.S. Highway 10 is broken into two segments by Lake Michigan. Travel between the two segments is possible on a seasonal basis via the ferry SS Badger between Ludington, Michigan, and Manitowoc, Wisconsin. The ferry route and link are not part of the U.S. Highway system.

The eastern terminus of U.S. Highway 10 is in Bay City, Michigan, at its interchange with Interstate 75 (near Highway 10's milepost 139 and Interstate 75's milepost 162). The western terminus of U.S. Highway 10 is in the town of West Fargo, North Dakota, at its interchange with Interstate 94.

In the state of North Dakota, Highway 10 runs for about eight miles (13 km), from Interstate 94 at Exit 343 to the Red River of the North. It is one of the primary east–west streets in West Fargo and Fargo, and is called Main Avenue for its entire length in North Dakota. At the Red River, U.S. 10 crosses over a bridge to Moorhead, Minnesota.

US 10 is a major divided highway for almost all of its length in Minnesota. The road enters Minnesota in Moorhead and travels through Detroit Lakes, Wadena, Little Falls, St. Cloud, Elk River. It becomes a Freeway in Anoka and passes through the northern suburbs of Minneapolis and St. Paul, It enters St. Paul duplexed with Interstate 35-E and exits St. Paul duplexed with U.S. Route 61. It leaves Hwy-61 just north of Hastings, shortly before entering into Wisconsin.

U.S. 10 enters Wisconsin at Prescott and travels southeastward passing Neillsville, Marshfield, Stevens Point, and Appleton before reaching its eastern terminus near the Lake Michigan shore in Manitowoc. Ferry service between the western and eastern portions of U.S. 10 is provided on a seasonal basis by the ferry S.S. Badger. U.S. 10 is now a 4 lane divided highway from STH 80 2 mi (3.2 km) south of Marshfield to Interstate 39. This allows travelers to bypass Auburndale, Blenker, Milladore, Junction City, and downtown Stevens Point. This completes the plan to upgrade U.S. 10 to a freeway or expressway status from Marshfield to Menasha. U.S. 10 is an expressway between Stevens Point and Waupaca. It has been upgraded to a freeway in the Waupaca area and is also a freeway between Fremont and Appleton. There has been a plan suggested to upgrade the U.S. 10 section between Marshfield and Neillsville to expressway status.

The Western terminus of U.S. 10 in Michigan is Ludington. U.S. 10 is concurrent with U.S. 31 from Ludington to Scottville before US-31 heads north. The road then heads east through Baldwin and Reed City before it becomes a freeway west of U.S. 127 near the junction with highway M-115. U.S. 127 and U.S. 10 overlap for a short distance near Clare. U.S. 10 bypasses Midland and terminates at I-75 in Bay City.

US 10 has had alternate routes designated in the past, but none are active as of 2004.

Between 1926 and 1934, there was a pair of alternate routes between St. Cloud, Minnesota and Moorhead, Minnesota. U.S. Route 10N, the northern route, connected St. Cloud, Little Falls, Motley, and Detroit Lakes before reaching Moorhead. U.S. Route 10S ran from St. Cloud through Alexandria and Fergus Falls before rejoining U.S. Route 10N at Moorhead. In the mid-1930s, U.S. Route 52 was extended into Minnesota, and Route 10S was renamed to Route 52 (now Interstate 94). Route 10N was renamed to Route 10.

Originally, US 10 also passed through Montana, the Idaho Panhandle, and Washington, terminating in Seattle. The completion of I-90 and I-94 replaced US 10 along this route, although some sections of the old US 10 road still exist in such cities as Bismarck, Missoula, Spokane, and between Cle Elum and Ellensburg as State Route 10. The last section of Interstate 90 to be completed was between Coeur d'Alene and Wallace in the early 1990s. Much of this route was co-numbered as both I-90 and US 10 until the final completion of I-90 through Idaho. Some decommissioned sections of US 10 are designated Interstate 90 Business or Interstate 94 Business routes.

At the eastern end, US 10 originally went south from Midland, Michigan to Saginaw, Michigan on what is now highway M-47. It then joined up with US 23 in Saginaw, and continued south until it split from US 23 north of Flint, Michigan. It then continued south-east as the Dixie Highway to Pontiac, Michigan, where it became Woodward Avenue, now designated as M-1. From there, US 10 continued on an almost straight line to downtown Detroit, where it intersected with US 16, US 25, and US 12. It then took a two-block jog, and ended up at the Detroit–Windsor Tunnel to Canada.

In the 1970s, US-10 was rerouted off Woodward Avenue in the Detroit area and onto the John C. Lodge Freeway (formerly Business Spur 696, now M-10) and Telegraph Road. US-10 was truncated to Bay City, Michigan in 1987 at which point the Lodge Freeway was changed to M-10.

In 1925, US-10 was originally proposed to run from Detroit through Chicago, and northwesterly into Wisconsin on what later became US-12.