Police were called to the home in the northern suburb of Broadmeadows about 2am on Tuesday, Detective Inspector Dean Thomas said.
Officers found the bodies of three males, aged 37, 32 and 17 and a 42-year-old woman with no signs of violence.
"We certainly don't know what has caused their death ... it's not obvious to us at this time," Insp Thomas told reporters at the scene.
"It may be from a drug overdose, it may not."
The bodies were found by a relative in the same area of the house, leading police to believe they were sitting together and there was no evidence to suggest there had been any violence inside the home.
Investigations will look at a range of causes including the possibility of a drug overdose and carbon monoxide poisoning, with police not ruling anything out, Insp Thomas said.
"It's unusual that we find four people deceased in the one property potentially from a drug overdose but we've got to keep an open mind until we can confirm that's the case," he said.
Police believe one of the victims lived at the home and three others were visiting.
Their bodies are yet to be formally identified.
Insp Thomas said police didn't believe the deaths were suspicious and a report would be prepared for the coroner.
The bodies were discovered by a man, who claims to be a relative of at least one of the victims.
The man, named as Corey by Nine News and described as a neighbour and believed to be the uncle of the 17-year-old, said he went to the home and knocked on the door but no one answered.
He says he looked through a window and saw the teenager lying on the floor.
"I've come home to find family members in the house deceased and it just tortured me, shocked me," he told Nine's Today program.
"I think (it was) an overdose but I'm not too sure exactly."
Distressed family and friends comforted each other when they turned up at the property. (Joel Carrett/AAP PHOTOS)
Insp Thomas said it would have been "very confronting and very traumatic" for the man to have discovered the bodies.
The 37-year-old man, 42-year-old woman and 17-year-old boy were known to police.
Corey was joined at the scene by several distressed people believed to be family members and friends as forensic crews arrived to gather evidence.
One man tried to enter the scene, but was stopped by officers.
Devastated relatives and friends were seen hugging and later escorted inside the home by police.
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