The county was formed in 1920 from Charlton, Pierce, and Wayne counties and was named for Benjamin D. Brantley, a member of a prominent local family, although some historians claim the name honored State Senator William Goodman Brantley of Brunswick.

Since the Okefenokee Swamp is to the south and west of the county, passage through Brantley County was essential to the railroads running from the coast through the southern part of the state.