The railroad reached the area around 1898, but it wasn't until 1901, with the construction of the post office, that the foundation of the site, named after Senator Chauncy M. Depew, was laid. Curiously, it was not until 1905 that land was sold where people could settle to benefit from the post office.
In 1911 the discovery of oil triggered a real boom. Standing on the deserted Main Street today, it's hard to believe how lively this town used to be: 1,126 residents called Depew home until the Great Depression of 1929.
Depew was the first place to be detached from Route 66: as early as 1928, the highway was relocated to its present location, eliminating the U-shaped detour through town.