Six fire engines and around 40 firefighters tackled a fire at a shop with flats above on Bloomfield Road in Plumstead.
The ground floor of the building was destroyed by fire. Two adults and two children left a first-floor flat before the Brigade arrived. There were no reports of any injuries.
The Brigade was called at 0047 and the fire was under control by 0254. Fire crews from Plumstead, East Greenwich, Sidcup and surrounding fire stations attended the scene.
The cause of the fire is under investigation.