Fire crews were called to the Middleton Rd property about 9.50am.
The occupants of the house escaped before the fire took hold. It is thought to have damaged almost all of the house.
A witness living two doors down said he was drinking his morning coffee when he heard the sound of windows cracking and breaking.
"I went out to my balcony and saw flames coming out of the broken windows of the house."
The man ran to the road and saw the occupants of the home, a woman and her children, on the road safely.
"They moved there [to the property] not long ago.
A second witness from a neighbouring house said she came outside to the sound of windows breaking.
"I thought it was just a small kitchen or chimney fire; it wasn’t that serious.
"Just as the first fire truck arrived the house all of a sudden really went up in smoke. They got here really fast and arrived at a good time."
St Kilda Senior Station Officer Pete Douglas said crews from Lookout Point and St Kilda were initially called to a couch on fire.
However, when they saw the size of the fire, backup from Roslyn and Central City was called.
"All occupants were out safely, but it is a very traumatic situation for them all."
Crews used breathing gear and hoses to enter the house from the front and back.
"We’re looking at 100% smoke damage throughout the property ... and 60% to 70% fire damage, if not more."
Fire investigators would be called in to investigate the fire, but Mr Douglas said it was not thought to be suspicious.
It is one of many house fires in the region in recent months, prompting a safety message from Fire and Emergency New Zealand.
Earlier this month, building fires in South Dunedin and Brockville caused significant damage to the properties involved.
Last month, firefighters also battled extensive house fires in Port Chalmers, Caversham and Concord.
"Check your smoke alarms, ensure they’re properly installed and make sure you have enough in your home", Mr Douglas said.
"Thankfully these guys [at Middleton Rd] had two smoke alarms which meant they got out of the house safely."
