The F-18, a twin-engine supersonic aicraft used by the US Navy, came down in waters near Naval Air Station Key West in Florida on the US east coast.
Officials say both the pilot and the weapons systems specialist were taken to the hospital after they ejected from the jet, but couldn't confirm their status.
The Naval Air Station at Key West is the southernmost base in the continental U.S. According to military.com, a second pilot also ejected.
A blaze engulfed the jet before it crashed around a mile away from the runway, a witness told Local 10 News. "Search and rescue efforts are ongoing".
"It was going in to land, and all of a sudden, the whole thing flipped sideways and I saw a fireball", witness Barbie Wilson told CBS News.
Photos posted on Twitter show a rescue helicopter hovering over the F-18. Dave Hecht, a spokesman for Naval Air Forces Atlantic.
The jet was part of Virginia-based Strike Fighter Squadron 213.