[4] The route connecting Athens and Marietta has been a state highway since the system's creation in Ohio in the 1910s.

[8] By 1935, the mainline of US 50 was signed along US 50S between Athens and Pike, West Virginia and the former US 50N became U.S. Route 50 Alternate (US 50 Alt.).

[9][10] A temporary ferry between Newport and St. Marys was utilized until the new Hi Carpenter Memorial Bridge opened in 1977.

's eastern terminus was moved back to Ellenboro, albeit at an interchange with the US 50 freeway.

At least part of the route of 550 is based on the original Marietta-Chillicothe Stagecoach Road.