Police said a 3-year-old boy was found dead inside the home. A 9-year-old girl was taken to Children's Hospital of Philadelphia where she died.
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"Looks like this is going to be a multiple fatality incident, incredibly tragic for us, and my heart goes out to the families involved," Philadelphia Fire Commissioner Adam Thiel said. "It's a tragic morning."
Neighbors called 911 to report a fire shortly after 1 a.m. Saturday on the 1500 block of South 30th Street.
Fire crews arrived to intense flames shooting from the row home.
Firefighters said three people jumped from the top floor to safety.
Crews also rescued two others who were trapped, including the 9-year-old girl who later succumbed to her injuries.
A 9-month-old child remains in critical condition at CHOP, suffering from smoke inhalation and burns, according to authorities.
"I heard the father outside screaming, holding the baby, and I thought I was dreaming or I heard the TV. I turned the TV off, opened the door and there was a burst of flames coming out this house," a neighbor said.
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A 24-year-old woman is hospitalized in critical but stable condition. Police said she jumped from a second floor of the home, then suffered second degree burns on her body when she attempted to get back into the residence to get the children.
Neighbor Terek Barnes said he called 911 and then ran across the street.
"Heard glass shatter in front of the house. All I seen was somebody jump out the window and then I see somebody else behind her. Next thing I see is fire spreading going from the first floor to the second, I ran outside with no shoes on to help," Barnes said.
Barnes said he carried the 24-year-old woman across the street to his home. He said he also tried to go back to the home to try to save the children.
"I told them to run to the back, 'come to the back, I'm right here. Just please come to me, follow my voice,' and I didn't see anybody coming," Barnes said.
Police said a 30-year-old man is in stable condition with burns and smoke inhalation at Penn Presbyterian Medical Center.
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A man in his 50s is in critical condition at Penn Presbyterian with smoke inhalation.
"It was horrible. It was coming out the windows like a furnace and nobody could get close to the house," a neighbor said.
There is no word on the relationship between the victims.
A cause of the fire is under investigation.
The Red Cross is helping those in neighboring row homes who have been displaced.