Fire Rescue Victoria was called to an address in Sydenham on Sunday night to find smoke and flames billowing from the brick home's roof.
"Wearing breathing apparatus, firefighters worked to gain access into the house to extinguish the fire and search the house for occupants," FRV said in a statement on Monday.
Firefighters found the three children in the house and they were rushed to hospital with life-threatening injuries.
Victoria Police's arson and explosives squad is investigating what sparked the blaze, which occurred after a large bang was heard by local residents.
"The area has been cordoned off and a crime scene established," Victoria Police said in a statement.
"No one else was injured in the fire, with investigators working to determine if anyone else was present in the home at the time or just prior to the fire."
Detectives and an arson chemist would attend the scene on Monday morning, police said.
Fire Rescue Victoria said the properties either side of the house were not affected but would be checked for smoke damage.