Flight QF9, which was traveling from Melbourne Friday, was diverted to Muscat, Oman for the medical emergency but was unable to land in time to save the man.
"Our crew did everything they could, including helping perform CPR with a doctor who was on board, but unfortunately the passenger passed away before the flight landed," the Australian carrier said in a statement.
"Our thoughts are with the passenger's family."
Qantas declined to give further information about the passenger and the circumstances around his death for privacy reasons, but the Sydney Morning Herald reported that he suffered a suspected heart attack.
Another passenger on board the plane told the Herald that the Airbus A380 "started to make a very fast descent".
"The patient was being treated on the floor in the middle of everyone. He died before they could land and when they landed a string of people came on board to examine the situation.
"About an hour later they removed the body and distraught wife and travelling companions."
Earlier this week, the same flight from Melbourne to Dubai was three hours into its journey when one of its engines had a "slight vibration issue" and the aircraft was diverted to Sydney, the airline said.