Emergency services were called to St Georges Road, near Watkins Street, in North Fitzroy just after 11.30pm yesterday.
Police believe the car struck a pole and rolled.
The 22-year-old driver, who was the only person in the car, died at the scene.
Police remain on-site and an investigation into the circumstances surrounding the crash is underway.
Saint George's Road remains closed in both directions between Reid and Church Street.
Vic Traffic has advised motorists to allow extra time for travel and seek an alternative route.
Trams along Route 11 are also affected.
Anyone who witnessed the crash, with dashcam or information is urged to contact Crime Stoppers on 1800 333 000.