In the U.S. state of Missouri, U.S. Route 50 is a major east-west route.

US 50 enters Missouri from Kansas along Interstate 435 around Kansas City and then it runs concurrently with Interstate 470 to Lee's Summit. It then runs as an expressway to Sedalia. From Sedalia to California, US 50 becomes a 2 lane undivided road. It then resumes as an expressway from California to Jefferson City. It has a concurrency with US 63 for 12 miles from Jefferson City. From the end of the concurrency with US 63 to Union, the road is 2 lanes. At Union, US 50 is routed along Interstate 44 up to Sunset Hills, then it heads east and merges with U.S. Route 61 and U.S. Route 67. These three concurrent U.S. routes stay this way until after the interchange with Interstate 55, then 61 and 67 split off, leaving 50 to merge with Interstate 255 to cross the Mississippi River via the Jefferson Barracks Bridge in St. Louis.

Until 1926, US 50 in Missouri was Route 12.