Fifteen fire engines and around 100 firefighters tackled a flat fire on Hatcham Park Mews in New Cross.
Part of the first floor and most of the second floor of a residential block were damaged by fire. The roof of the building was destroyed. There were no reports of any injuries. 34 residents were relocated to a nearby rest centre and hotel.
Two of the Brigade's 32-metre turntable ladders were used as water towers to tackle flames from height.
Station Commander Patrick Ackroyd, who was at the scene, said: "Crews worked hard in challenging conditions to bring the fire under control and are expected to be on scene throughout the morning.
"The fire generated a large plume of smoke, particularly around the junction of New Cross Road and Queens Road. We asked people who live or work nearby, to keep windows and doors closed.
"The incident also caused significant traffic disruption, so we asked people to avoid the area where possible."
The Brigade's Control Officers took the first of 12 calls to the fire at 1627 and mobilised crews from New Cross, Peckham, Greenwich, Deptford and surrounding fire stations to the scene. The fire was under control by 0648.
The cause of the fire is under investigation.