The fire broke out shortly before 2:40 a.m. inside a large apartment building on 40th Street in the Sunnyside section of the borough.
Fire officials said the blaze started on the building's second floor before spreading to the third floor.
Two residents were found on the second floor. One victim was pronounced dead, while the second was transported to a nearby hospital in critical condition.
A firefighter also suffered injuries while battling the fire and was taken to an area hospital for treatment.
Residents described waking up to frightening conditions as smoke filled the building.
"I woke up to heavy smoke," one resident told Eyewitness News.
The cause of the fire remains under investigation.
----------
* Get Eyewitness News Delivered
* More Manhattan news
* Send us a news tip
* Download the abc7NY app for breaking news alerts
* Follow us on YouTube