The crash happened shortly after 1 a.m. in the Scarborough Junction area, near Kennedy and Eglinton avenues.
According to Toronto police, the motorcycle rider was thrown from their bike and was unconscious.
Rescuers rushed the victim to the hospital with an emergency run.  His injuries were pronounced fatal, police said.
The driver, who police said was a man in his 30s, was pronounced dead at the hospital.
The other driver remained at the scene.
Kennedy Street at Transway Crescent is closed as Traffic Services investigates.  TTC services are also affected by this closure.
Anyone with information should contact Toronto police at 416-808-1900 or Crime Stoppers anonymously at 416-222-8477 (TIPS) or www.222tips.com.