Fire and police officials say the two were pulled from the home at 1945 Winnipeg St., by a passerby around 1:45 a.m. CST.
Deputy fire chief Gerard Kay said it was "an inferno" when fire crews arrived.
"They probably would have taken a lot of heat and a lot of flame," Kay said.
Police and ambulance workers tried to resuscitate the two victims, but they were pronounced dead in hospital.
"Unfortunately, this had gotten way out of control. Even with the victims being out before we got there, they succumbed to their injuries," he said. "It's very heartbreaking to see this situation occur."
As of 6:20 a.m. CST, there was still the possibility that a third person had been in the house, Kay said. That person had been in a back bedroom, but may have had time to get out.
The fire was intense and tough to fight, Kay said.
"A lot of flame," he said.
"It seemed the more water they poured on it, the bigger the flames grew, which is very unusual. They said they had flames through the floor from the basement; they had flames coming out from the attic space."
Fire crews finished mopping up at the scene, near Winnipeg St. and Victoria Ave., around 6 a.m. CST.
Due to all the water poured on the site and a temperature of about -24 C, "it looks like an ice palace" and conditions will be slippery for any drivers in the area, Kay said.
Major crimes investigators from the city police will be investigating the fire, as it involved fatalities.