The 48-year-old man, whose identity was not immediately released, was inside his 16th-floor apartment at 1365 Fifth Ave., near 112th Street, when a fire erupted about 12:20 a.m., police and the FDNY said.
He was found in the kitchen and rushed to Mount Sinai Hospital, where he was pronounced dead, police said.
The man appeared to have suffered a heart attack and the fire appeared accidental, sources said.
Fire marshals were still investigating what sparked the fire and the medical examiner's office will determine the man's cause of death, police said.
The approximately 78 firefighters who responded were able to bring the fire under control by about 1 a.m., an FDNY spokesman said.