The fire erupted around 5:30 a.m. on the 7300 block of Ryers Avenue, near Shelmire Street.
Officials said heavy smoke and flames were pouring from the roof of the home when fire crews arrived.
The view from Chopper 6 showed firefighters pouring water on the heavily-damaged home.
Neighbor Gina Palesino said she woke up to her husband, who was frantic after seeing the fire.
"He knocked on my door and said 'Fire! Fire!' and I come out, open the door, and I see all the flames," she said.
Assistant Fire Chief Harry Bannon said when personnel arrived at the scene, a man and a woman were outside of the home. Bannon said one of them jumped from a second-floor window to escape and one exited from the first floor. They were both taken to Jefferson Torresdale Hospital by police.
Bannon said the two who had escaped told firefighters there were two other adults trapped inside.
According to Bannon, firefighters entered the home to find heavy flames on the first floor. They rescued an unconscious 21-year-old man and an unconscious 82-year-old woman who were taken by medics to Jefferson Torresdale Hospital in critical condition. The two were subsequently airlifted to Jefferson University Hospital where they are currently listed in critical condition.
The fire was placed under control just before 6:30 a.m.
There was no immediate word on the cause of this fire.
The Fire Marshal is at the scene to investigate the possible cause of the blaze.