The London Fire Brigade (LFB) said eight fire engines and around 60 firefighters were sent to Collingwood Road, Sutton, at 6.55pm on Thursday.
Crews faced an “intense blaze” throughout the whole of the ground floor of the property.
Four young children were taken out of the house and given CPR by firefighters at the scene before being taken to two south London hospitals where they died.
The fire was under control by 8.36pm and the cause is under investigation.
Superintendent Rob Shepherd said: “The thoughts of everyone at the South Area Command Unit are with the family and friends of these four young children, who have suffered such a devastating and tragic loss tonight.
“I know these sentiments will be shared by the local community, Sutton and London as a whole.
“We remain on scene with our emergency service colleagues and will be working through the night and beyond. At this very early stage the cause of the fire is unknown and will be investigated.”