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A man who was knocked off his motorbike and who may have been struck by multiple vehicles, including a police car, has died in western Sydney overnight.

Shortly before 2am, the motorcycle, believed to be a smaller scooter, was heading east along the M4 near Church Street, Parramatta.

It collided with a white Kia sedan, and the rider was thrown onto the road.

A motorcyclist is dead after being struck by a police care on the M4 near Parramatta.

NSW Police Commissioner Brett McFadden said the Kia had crossed from lane two into lane one just before the collision in that lane.

A Toyota Echo is believed to have hit the rider on the road, while a ute also crashed into the wreckage.

A marked police car then hit the rider.

Police and paramedics provided emergency CPR and the man was taken to hospital but could not be revived.

He is believed to be aged in his 20s or 30s but is yet to be formally identified.

Police say the police car was not pursuing the motorcycle.

Three drivers, including a NSW Police senior constable, were also taken to hospital for mandatory testing.

Investigators will speak to them at a later date.

A critical incident investigation into the crash is underway.

NSW Police said the police car was not on urgent duty and did not have its lights or sirens activated at the time.

The M4 remains closed with traffic backed up for 12km and more.

"There had been no interaction with and no pursuit of the motorcyclist or any other vehicle," police said in a release.

"Initial information is the officers were returning to the station when the incident occurred."

McFadden said early indications were that the motorcycle's low speed could have been a factor in the crash, with the rider travelling "well below" the 90km/hr speed limit.

"It's a tragic set of circumstances for all concerned," he said.

"Everyone involved in this incident is shaken."

Any witnesses in the lead-up to or during the crash are urged to contact Crime Stoppers on 1800 333 000.

Two citybound lanes of the M4 have reopened at the site of the crash, while two remain closed.

Significant delays continue citybound on the M4, Great Western Highway and other roads including the M7 and M2.

Motorists and bus travellers are still advised to allow plenty of extra travel time.

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