The collision, which involved a motorbike and a silver Honda, happened on the Prudhoe Bypass section of the A695, at around 11.57am.
Emergency services, including the air ambulance, attended but the rider of the motorcycle was pronounced dead at the scene.
The male driver of the Honda was taken to the Royal Victoria Infirmary (RVI) in Newcastle where he died as a result of his injuries.
A male front-seat passenger from the Honda was also taken to the RVI, where he is being treated for serious but non-life-threatening injuries.
Specially-trained officers are currently supporting the families of all those involved through this difficult time.
Police are appealing for any witnesses to the collision or anyone who was in the area and might have dash-cam footage to contact them on either 101 or [email protected] quoting log 476 06/10/18.