The costly plane was completely destroyed in the crash during training on Friday, according to one official, who also said, "It's a total loss."
Images posted on social media show a plume of black smoke rising above what users described as the crash site.
It was an F-35 "B" variant, which is used by the Marine Corps, and it is capable of taking off from a short runway and landing vertically.
No serious injury was reported after the incident and according to the Beaufort County Sheriff's Office, the pilot safely ejected and was being evaluated for injuries.
The aircraft will become the main fighter aircraft for the Marine Corps, Air Force and Navy, according to a military official.
Although unit costs vary, the price tag of F-35s is estimated at $100 million each. Future production lots of F-35s are predicted to decrease slightly in price.
The crash comes just one day after a Marine F-35B fighter conducted its first-ever airstrike in Afghanistan against what the US described as a Taliban target.
The Marine F-35B "Lightning II" had taken off from the US Navy amphibious assault ship USS Essex, which was operating in the East Arabian Sea.
The F-35 program, which was first launched in the early 1990s, is regarded as the most expensive weapons system in US history, with its costs estimated to be around $400 billion and a goal to produce 2,500 aircraft in the coming years.
Overall program costs are expected to rise to $1.5 trillion if servicing and maintenance costs are factored in over the aircraft's lifespan through 2070.
The plane's state-of-the-art features - radar-dodging stealth technology, supersonic speeds, close air support capabilities, airborne agility and a massive array of sensors - enable pilots to have unparalleled access to information.
However, the program has experienced numerous delays, cost overruns and setbacks, including a mysterious engine fire in 2014 that prompted commanders to temporarily ground the planes.