Police said a white truck was driving Altona-bound on the Western Ring Road about 4pm when a ramp came off the back of it.
The object careered into the Greensborough-bound lanes of the freeway and struck a sedan near the Furlong Road exit, in St Albans.
The driver of that car, who is yet to be identified, died at the scene.
Police are urgently hunting the driver of the truck, who failed to stop and was last seen travelling Altona-bound on the freeway.
It is not known whether the driver of the truck knew what had happened.
All Greensborough-bound lanes of the Ring Road have been closed between Ballarat Road and Sunshine Avenue.
The road is expected to be closed for several hours and motorists are advised to avoid the area.
Anyone who witnessed the incident or who has footage, is urged to contact Crime Stoppers on 1800 333 000