The county deputy coroner confirmed the fatalities after the US Air Force reported than a C-130 aircraft had gone down at the intersection of Highway 21 and Crossgate Road at around 11.30am local time on Wednesday.
A photo tweeted by the Savannah Professional Firefighters Association showed its wrecked tail end, with a plume of black smoke rising from the wreckage and fire spreading through a roadside field.
Emergency services remain on the scene, a few miles from Savannah Hilton Head International Airport.
The plane was from the Air National Guard 156th Air Wing based in Puerto Rico and was bound for Davis-Monthan Air Force Base in Arizona.
US media reports that there were five people on board.
Local roads have been closed and some flights at the airport – from where the smoke is visible – have been affected.
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It is not yet known what caused the crash.