The shooting took place at the Love Machine nightclub in Prahran - just outside the city, at 3.20am local time (5.20pm GMT), according to Victoria Police.
The victim, a 37-year-old security guard from Narre Warren South, died in hospital from his injuries.
Three other people were taken to hospital following the incident, with a 28-year-old man remaining in a critical condition.
Two men, 29 and 50, sustained non-life threatening injuries.
Three of those who were shot were security guards at the nightclub, the fourth was a man queueing to enter.
Police are investigating reports that a black Porsche SUV was involved in the shooting, which was found burnt out in Wollert, north of Melbourne.
Detectives and police are at the scene and no arrests have been made. A spokesman said there was no indication yet that the attack was terror-related.
Andrew Stamper, of Victoria state police, said: "It would appear that shots have been discharged from a carin this area into a crowd standing outside the nightclub.
"These things are still incredibly rare and there's nothing to indicate at the moment that this is part of a broader agenda."
Writing on Facebook, Love Machine host Steve Yousif wrote: "Overwhelmed with all your calls and texts, nothing but love for you all.
"What happened last night was uncalled for and devastating. For some of you it was a night out, the rest of the Love Machine family lost a beautiful soul today."https://www.geezgo.com/sps/56371
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