Flames broke out around 2:45 a.m. at a high-rise building on Casals Place in Co-Op City.
Police said an 85-year-old was found unconscious and unresponsive inside his apartment, and a 49-year-old woman was suffering from smoke inhalation in the lobby.
Both victims were rushed to Jacobi Medical Center, where the man was pronounced dead.
Two firefighters were also treated for minor injuries on the scene.
The cause of the fire is under investigation.
The FDNY battled two other deadly blazes early this morning in Brooklyn and Queens.