One firefighter was hurt battling the two-alarm blaze, which has been labeled suspicious.
More than 100 firefighters responded to the scene of the vacant three-story home on Osbourne Place in the Morris Heights section just after midnight to find flames shooting through the roof.
It took just over two hours for them to get the fire at the three-story private house under control. An internal collapse was also reported, believed to be the third floor.
The injured firefighter was taken to St. Barnabas Hospital to be treated for a minor injury.
The cause of the fire remains under investigation, but it is considered suspicious because neighbors say a homeless man was squatting inside and that they heard an argument shortly before the flames erupted.
"We had some neighbors say that about 10:30, they heard this person arguing with some people, and they haven't seen him since," FDNY Assistant Chief William Seelig said. "So again, we made the fire suspicious. Our Fire Marshals are on the way to try and locate the individual in question and interview him to see what they can determine."
Authorities were still looking for that homeless person, and it was unclear if he was inside when the fire broke out.