Police said a vehicle collided with a mobility scooter near the intersection of Francis and Ballarat Streets in Yarraville just after 11.30am.
The male mobility scooter rider, 88, died at the scene.
9News understands the truck driver is cooperating with police.
Police are working to establish the circumstances of the collision.
Both lanes of Francis Street are shut down to traffic between Hyde Street and Williamstown Road, causing heavy congestion on nearby roads.
Resident and business access remains available on either side of the closure.
Drivers are urged to avoid using Francis Street in the coming hours.
Alternative routes include the West Gate Bridge, Napier Street, Buckley Street, Geelong Road, Hopkins Street, Moore Street and Ballarat Road.
