The crash occurred just before 7am at Dry Creek.
Police say the West Lakes man, 19, was rushed to the Lyell McEwin Hospital with "critical head injuries". He was pronounced dead on arrival at hospital.
West bound traffic was brought to a standstill, just after the Port Adelaide flyover.
Police are looking for a silver or maroon 1990s Nissan Skyline in relation to the incident. It is possible the driver was unaware of the accident.
Witnesses said the motorcyclist came across the overpass travelling west and the Nissan turned left off Port Wakefield Rd slipway before attempting to merge into traffic.
Paul Schubert, who was driving on the Salisbury Highway, said he saw the Nissan "cut across" several lanes, causing the motorcyclist to swerve dramatically and crash in to a centre guard rail.
"The Nissan (driver) was driving erratically before the accident," he said. "With wet roads at this time of the morning (driving like that) is absolute stupidity."
RIP Mate...thanks to an absolute COCKHEAD!!!
RIP and condolences to the family of the poor soul.