"The F-16 pilot ejected to safety and was being treated for his injuries," officials at Shaw Air Force Base was quoted as saying.
Two people aboard the two-seater Cessna C150, were killed. The collision happened at about 11:00 local time (16:00 GMT) roughly 11 miles (17km) north of Charleston.
The National Transportation Safety has launched an investigation into the crash.
Military jets from Shaw Air Force Base, outside of Columbia, routinely fly training missions over eastern South Carolina and the Atlantic.