In 1912 the route that would become US 50 was designated Main Market Route 45. In 1923, Main Market Route 45 was decommissioned and SR 7 replaced it from Indiana to Cincinnati. SR 27 from Cincinnati to Milford and SR 26 from Milford to Athens. US 50 replaced SR 144 from Athens to Coolville and SR 7 from Coolville to West Virginia state line. At this time the route that later became US 50 was paved between Indiana and Highland–Ross county line. In 1926 US 50 was signed on a route similar to today. The current route that US 50 between Athens and West Virginia became US 50S in 1929, with the current SR 550 becoming US 50N. US 50S and US 50N would be replaced with US 50 and US 50 Alt, in 1935.