The route crosses Lake Michigan by ferry (the SS Badger) between Ludington, Michigan, and Manitowoc, Wisconsin. US 10 is one of only two US Highways that include a ferry ride in the route (US 9 is the other). Formerly, US 16 also had a ferry connection between Muskegon, Michigan, and Milwaukee, Wisconsin; ferry service on this route was restored and now runs as the Lake Express. All U.S. Highway ferries may be eliminated if long tunnels or bridges are constructed to supplant them.
As of 2004, the highway's eastern terminus is in Bay City, Michigan, at an intersection with Interstate 75 (US-10 mile marker 139, I-75 mile marker 162). Its western terminus is in West Fargo, North Dakota at an intersection with Interstate 94.
U.S. Highway 10 enters Michigan after it crosses Lake Michigan from Manitowoc to Ludington. U.S. 10 is concurrent with U.S. 31 from Ludington to Scottville before Highway 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.
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, Minnesota, Motley, Minnesota, and Detroit Lakes, Minnesota before reaching Moorhead. U.S. Route 10S ran from St. Cloud through Alexandria, Minnesota and Fergus Falls, Minnesota 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.
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 1970's, US-10 was rerouted off Woodward Avenue in the Detroit area and onto the John C. Lodge Freeway (formerly Business Spur 696) and Telegraph Road. US-10 was truncated to Bay City, Michigan in 1987 at which point the Lodge Freeway was changed to M-10.