The Federal Aviation Administration said in a statement that the fighter jet collided with a two-seater Cessna about 17 kilometres north of Charleston, raining down plane parts and debris.
Officials said they have no reason to believe anyone survived the crash though bodies have not been recovered. A search area of about 12 kilometres is being combed.
The jet pilot, Maj. Aaron Johnson, was taken to hospital for observation, said Lt. Jenny Hyden, a base spokeswoman. She did not disclose his condition. No one else was on board the single-seat jet which was conducting instrument training, according to Col. Stephen Jost. There were no ammunitions aboard the jet.
Jost said more details will be available after an investigation.
"There are 100 factors that could have been in play," he said.
No injuries on the ground or damage to residential or commercial buildings have been reported.
A witness reported that the military plane broadsided the smaller Cessna, said Berkeley County coroner Bill Salisbury. He said debris was scattered over a wide, marshy area.
"We have airboats and boats that are designed to run in the mud," Salisbury said.
The National Transportation Safety Board has opened a probe into the collision, said Keith Holloway, a spokesman for the board.
The Air Force has flown F-16s since the 1970s, though very few active-duty squadrons still fly them. F-16s from Shaw Air Force Base, routinely fly training missions over eastern South Carolina and the Atlantic.
The smaller plane was a Cessna 150, according to the FAA, a plane that debuted in 1959 and remains one of the most common single-engine planes in the U.S.
Linda Tyler, a resident of Lewisfield Plantation in Moncks Corner, said she heard a large "kaboom" in the morning. Later police vehicles blocked the entrance gate to her community, she said.
Wayne Ware told The Post and Courier of Charleston he was going for a walk when he heard the crash.
"I turned around, and I saw the jet. Pieces started falling out of the sky," Ware said, telling the newspaper the jet's engine landed at a campground.
Many F-16s still in service in the U.S. are assigned to Air National Guard units, but Col. Cindi King of the South Carolina Air National Guard said the F-16 involved in the crash did not belong to the Guard.