In Worland, US 16 splits off from US 20 and heads east over Powder River Pass on its way to the city of Buffalo.

US 16 then runs east concurrently with I-90 between Gillette and Moorcroft before heading southeast to the towns of Upton and Newcastle.

In Rapid City, a truck bypass runs along Catron Boulevard and Elk Vale Road up to exit 61 on I-90.

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 U.S.

In 1938, reflectorized discs were placed on US 16 every 100 feet (30 m) from Detroit to Lansing, resulting in fewer nighttime traffic accidents.

U.S. Highway 216 (US 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.

Most of the stretch through Faribault County was a relatively narrow two-lane highway with wide gravel shoulders that has been widened at least two times since US 16 was decommissioned.

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, as the Crazy Horse Memorial Highway.