The crash, involving a car and a motorcycle, occurred on Lushington Hill near the junction of Park Road, Wootton, shortly after 11pm.
The motorcyclist and car driver both died as a result of the crash and Lushington Hill was closed for more than six hours.
Ambulance and police attended the scene, along with Isle of Wight Fire and Rescue Service, which was sent to help free the casualties.
Police have appealed for witnesses following the collision.
*A spokesman said: "The incident happened shortly after 11pm last night (Tuesday) at the junction of Park Road and Lushington Hill and involved a light blue Toyota Rav4 4x4 and a white Yamaha R6 motorcycle.
"The rider of the motorcycle, a 20-year-old man from Newport, sustained fatal injuries and died at the scene. His pillion passenger, an 18-year-old man also from Newport, was thrown from the motorcycle and sustained serious, but not life-threatening injuries. He was taken to St Mary’s Hospital in Newport where he remained overnight.
"The driver of the Rav4, a 46-year-old man from Ryde, was fatally injured in the crash and died six hours later at St Mary’s Hospital."
Anyone with any information is asked to contact Sergeant Darren Ord at Hampshire Constabulary’s Road Death Investigation Team at Eastleigh on 101, quoting Operation Beckley.