Mitchell was established in 1900 when the Chicago, Burlington & Quincy Railroad extended westward, and was incorporated as a city in 1902. It is named for nearby historic Fort Mitchell, itself named for Union Army Brigadier General Robert B. Mitchell.

Mitchell, population 1,548 in 2020, hosts the Scotts Bluff County Fair (organized since 1887) and is home to the former Western Sugar storage facility, a reminder of the region's long sugar-beet farming heritage.