US 16 originally connected Detroit with Yellowstone, including a ferry link across Lake Michigan between Muskegon, Michigan, and Milwaukee, Wisconsin.
In Michigan, the route was in use long before automobiles and was known to white settlers as the Grand River Road, and prior to the designation of US Routes in 1926, had been designated as M-16 in the 1920s from Detroit to south of Muskegon.
 In 1938, reflectorized discs were placed on US-16 every 100 feet (30 m) from Detroit to Lansing, resulting in fewer nighttime traffic accidents.
 Other states would later do the same on their roads.

US 16 initially crossed the South Dakota – Wyoming state line west of Spearfish.
U.S. Route 216 was commissioned in 1930 as a loop off US 16 to the south between Rapid City and Moorcroft, crossing the state line west of Custer.
In 1934, US 16 was moved to the US 216 alignment, while the former US 16 became part of an extension of US 14.

In Michigan, most of US 16 was superseded by I-96 and a segment of Grand River Avenue in Detroit ultimately became M-5.
US 16 was later decommissioned in Wisconsin, Minnesota, and eastern South Dakota to its present termini.

Between Rapid City and Dexter, Minnesota, it has been supplanted by I-90.
In Faribault County, Minnesota the highway took on another number as the was already a county highway 16.
Residents of the county continued referring to the road as "16" or "old 16" and eventually the county renumbered it as Faribault County 16.
From the county's western border with Martin County, 16 continues East through the city of Blue Earth as part of 1st Street and Leland Parkway until it briefly combines with US-169/Grove Street.
One half mile south of that point at the intersection of Grove and 7th Streets, County 16 follows 7th Street and continues East to the border of Freeborn County.
Most of the stretch through Faribault County is a relatively narrow 2 lane highway with wide gravel shoulders that has been widened at least two times since US-16 was decommissioned.
East of Dexter it is now Minnesota State Highway 16 and Wisconsin Highway 16.
In South Dakota it was replaced by various state highways (including SD 38 and 248) and county roads: generally, in West River the old alignment was transferred to county responsibility entirely, while in East River it remained a state-maintained highway.

An older Alternate US 16 in South Dakota has become South Dakota Highway 240.

In South Dakota, in 2009, the South Dakota Department of Transportation designated US-16/US-385 between Custer and Hill City, which passes by the Crazy Horse Memorial, now being carved in the Black Hills, the Crazy Horse Memorial Highway.
This segment of US-385 is also a part of the George Hearst Memorial Highway.
US 16 originally connected Detroit with Yellowstone, including a ferry link across Lake Michigan between Muskegon, Michigan, and Milwaukee, Wisconsin. In Michigan, the route was in use long before automobiles and was known to white settlers as the Grand River Road, and prior to the designation of US Routes in 1926, had been designated as M-16 in the 1920s from Detroit to south of Muskegon.  In 1938, reflectorized discs were placed on US-16 every 100 feet (30 m) from Detroit to Lansing, resulting in fewer nighttime traffic accidents.  Other states would later do the same on their roads.
US 16 initially crossed the South Dakota – Wyoming state line west of Spearfish. U.S. Route 216 was commissioned in 1930 as a loop off US 16 to the south between Rapid City and Moorcroft, crossing the state line west of Custer. In 1934, US 16 was moved to the US 216 alignment, while the former US 16 became part of an extension of US 14.
In Michigan, most of US 16 was superseded by I-96 and a segment of Grand River Avenue in Detroit ultimately became M-5. US 16 was later decommissioned in Wisconsin, Minnesota, and eastern South Dakota to its present termini.
Between Rapid City and Dexter, Minnesota, it has been supplanted by I-90. In Faribault County, Minnesota the highway took on another number as the was already a county highway 16. Residents of the county continued referring to the road as "16" or "old 16" and eventually the county renumbered it as Faribault County 16. From the county's western border with Martin County, 16 continues East through the city of Blue Earth as part of 1st Street and Leland Parkway until it briefly combines with US-169/Grove Street. One half mile south of that point at the intersection of Grove and 7th Streets, County 16 follows 7th Street and continues East to the border of Freeborn County. Most of the stretch through Faribault County is a relatively narrow 2 lane highway with wide gravel shoulders that has been widened at least two times since US-16 was decommissioned. East of Dexter it is now Minnesota State Highway 16 and Wisconsin Highway 16. In South Dakota it was replaced by various state highways (including SD 38 and 248) and county roads: generally, in West River the old alignment was transferred to county responsibility entirely, while in East River it remained a state-maintained highway.
An older Alternate US 16 in South Dakota has become South Dakota Highway 240.
In South Dakota, in 2009, the South Dakota Department of Transportation designated US-16/US-385 between Custer and Hill City, which passes by the Crazy Horse Memorial, now being carved in the Black Hills, the Crazy Horse Memorial Highway. This segment of US-385 is also a part of the George Hearst Memorial Highway.
U.S. Route 16