It is also known as the Rex M. Whitton Expressway in the capital of Missouri, Jefferson City.

It runs as an expressway to Sedalia before becoming Broadway Boulevard and intersecting with US 65 (Limit Avenue).

From Sedalia to California, US 50 becomes a two-lane undivided road, where it has a concurrency with Route 5 from Syracuse to Tipton between Morgan and Moniteau counties.

From just west of Linn to Union, the road is two lanes.

US 61 and US 67 split off, leaving US 50 to merge with I-255 to cross the Mississippi River on the Jefferson Barracks Bridge in St. Louis.