At least five were confirmed dead, a US official said on condition of anonymity, adding that the number of fatalities could rise.
The Hercules C-130J aircraft went down about 11:30am (1530 GMT), shortly after takeoff from the Savannah/Hilton Head International Airport, about 175 miles southeast of Atlanta, officials said.
The plane, which was on a training mission, was headed to Arizona and was going to be essentially retired after Wednesday’s flight, Major Paul Dahlen, spokesman for the Puerto Rico National Guard, told Pentagon reporters.
“It was basically its last flight,” Dahlen said. “Although it was an older aircraft, it was in good mechanical condition. I think it was 50-plus years old, but it was still, with all of the modern updates of a regular C-130.”
Dahlen declined to say whether all nine aboard were dead, but acknowledged that images of the crash appeared to “speak for themselves.”
Of the nine on the plane, five were crew members and four were passengers who were military maintenance and operations personnel, all from the Puerto Rico Air National Guard.
The four-engine plane sent up a towering cloud of black smoke, with a tail wing coming to rest on a highway median, television images showed. A witness, Michael Garrett, told WSAV-TV the plane was upside down before it crashed.
“That plane really flipped over on its back, slowly, like it was in slow motion,” Garrett said.
Gena Bilbo, spokeswoman for the Effingham County Sheriff”s Department, told reporters: “It is an absolute miracle” that no vehicles were hit in the busy intersection at the crash site.
Senior Master Sergeant Roger Parsons, an Air Force spokesman, said at a news conference that the cause of the crash was under investigation.
The crash was at least the fifth deadly accident involving a US military aircraft since early April and the first of a US military C-130 since July, when 16 service members were killed in a Mississippi crash.
Roads in the area may be closed for weeks, Bilbo said.
The C-130 is a transport workhorse for the US military, and Parsons described the crashed aircraft as a cargo plane.