Officials believe the flames started as part of some kind of electrical issue.
The blaze broke out around 4:45 p.m. near 33rd Street and Ridge Avenue.
Deputy Fire Chief Bill Demski said crews arrived within four minutes to find heavy flames on the second and third floors, and reports that someone was still inside.
Man found dead after flames tear through Strawberry Mansion home
"We arrived four minutes after the initial phone call to find heavy fire on the second and third floor, with occupants saying there was somebody still inside," Demski said.
Two police officers tried to rescue the person before firefighters arrived, but were unable to reach him.
Two other people escaped the home, but a third person - a man about 40 years old - was found dead at the top of the stairs on the second floor, Demski said. The victim has not been identified.
Firefighters spent about 40 minutes extinguishing the flames. The fire spread to the home next door, which is now uninhabitable. At least one person from that house was displaced.
"It was a single alarm with extra resources added. The place had some unique features that allowed the fire to spread to the house next door," Demski said.
Meanwhile, a separate investigation is now underway after someone went through the first responders' gear and stole personal items, including the keys belonging to two firefighters.
"It was discovered that one of the firefighter's personal vehicles that was parked at the station was stolen, and we believe that is directly related to the keys that were stolen from the truck here on location," said Philadelphia Police Inspector D.F. Pace, who called the crime particularly egregious and upsetting.
"We have this character that's taking advantage of the public's trust, going through emergency vehicles and stealing from them," Pace added.
Anyone with information is asked to call police at 215-686-TIPS.