Flames erupted from the modern townhouse in Chadstone in Melbourne's southeast on Wednesday night.
About 30 firefighters arrived at the scene to find flames burning through the roof of the two-storey house.
Neighbours informed rescuers there were four residents unaccounted for inside the home, Fire Rescue Victoria Commander Paul Eckholdt said.
"It was a difficult rescue for firefighters, given that they had to force entry into the property initially and then wearing breathing apparatus, and the conditions being quite hot and with virtually zero visibility," he told ABC Radio Melbourne.
Firefighters searched through the smoke-filled home until they found two primary school-aged girls and a woman in her 30s in an upstairs bedroom.
"They were unconscious, so they were carried out and taken out to the front where Ambulance Victoria paramedics and firefighters were waiting," Cmdr Eckholdt said.
"They did have some burns, and they also had some airway burns as well."
The girls were rushed to the Royal Children's Hospital while the woman was taken to the Alfred, all with critical conditions.
Authorities are treating the fire as suspicious, with fire investigators and an arson chemist to attend the crime scene on Thursday morning.
The home, one of two on the block, remains taped off with most of the damage occurring at the rear of the property and police and firefighters remain on scene.
The fire razed the home's upper floor bedrooms and ensuite, and penetrated the roof causing a partial structural collapse, while the rest of property has smoke and water damage.
17°C