The small aircraft, a twin-prop Metroliner, crashed around 07:30 (05:30 GMT), shortly after taking off from Luqa airport on a flight to Misurata, Libya.
The victims' nationalities have not been released.
Early reports that they were officials from the EU's border agency have been denied.
Frontex said the plane was "not deployed by" them and said "none of their staff were involved".
Malta International Airport officials released a statement confirming the deaths. The airport is closed "until further notice".
Part of the burning wreckage ended up on a road outside the perimeter of the airport.
Eyewitnesses said that it took off before turning on its side and going "straight down into the ground".
Video shot from another plane at the airport shows flames and thick black smoke billowing from the site of the crash, next to the runway.
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