U.S. Route 50 (US 50) is a part of the United States Numbered Highway System that runs from West Sacramento, California, to Ocean City, Maryland. In the U.S. state of Indiana, it is part of the state road system. US 50 enters the state in Vincennes. The 171.38 miles (275.81 km) of US 50 that lie within Indiana serve as a major conduit. All of the highway is listed on the National Highway System. Various sections are rural two-lane highway, urbanized four-lane undivided highway and one-way streets. The easternmost community along the highway is Lawrenceburg at the Ohio state line. US 50 passes through urban areas, farmland and woodland.

Vincennes is a city in and the county seat of Knox County, Indiana, United States. It is located on the lower Wabash River in the southwestern part of the state, nearly halfway between Evansville and Terre Haute. Founded in 1732 by French fur traders, notably François-Marie Bissot, Sieur de Vincennes, for whom the Fort was named, Vincennes is the oldest continually inhabited European settlement in Indiana and one of the oldest settlements west of the Appalachians. The population was 16,759 at the 2020 census.