The four-engine plane sent up a cloud of black smoke, with a tail wing coming to rest on a median, television images showed.
Watch the full video on mobile here. The unit did not release the identity of the people on board the plane.
While performing a training mission, a U.S. C-130 "Hercules" cargo plane from the Puerto Rico Air National Guard crashed about 11:30 a.m. near the Savannah Hilton Head International Airport, according to the U.S. National Guard.
Highway 21 from GA 307 to Gulfstream Road is closed indefinitely. Roads will be shut down in the area Thursday and officials are asking people to avoid the area. Puerto Rico's National Guard has five other similar planes, two of which need maintenance and aren't being used, he said. He says "it nearly looked like it stalled and just went nearly flat right there in the middle of the highway".
"As far as we know, no cars were hit, which is an absolute miracle", said Gena Bilbo, spokeswoman for the Effingham County Sheriff's Office.
"I have seen videotape from a surveillance camera of the accident and the airplane is in a developing spin at the point of impact, which would only be possible if the pilot went below the mandatory flying speed or stalled the airplane", he said.
Authorities have not commented on the cause of the crash, saying that they are launching an investigation.
Mark Jones was nearby when he says he saw the plane low in the air.
Photo made available by the Chatham Emergency Services, GA., shows firefighters putting out a fire caused by a plane crash near the airport in Savannah, Ga., May 2, 2018.
Master Sgt. Roger Parsons, said multiple crew members were killed in the crash, but investigators were gathering information about who was on the plane.
"Please join me in thoughts and prayers for the victims, their families and the great men and women of the National Guard", President Trump wrote.
Maj. Paul Dahlen of the Puerto Rican National Guard told CNN that the plane had been on its way to Arizona to be decommissioned.
The airport said some flights were being affected by the "aircraft incident off property".
The US military has been rocked by a string of aviation accidents in recent weeks, including an F-16 crash near Las Vegas last month that killed the pilot. The Air Force said five is a standard crew for the WC-130.