RCMP say the incident happened around 6:30 pm PT when the bus with about 20 people onboard stopped at a bus stop on Baron Road behind the Dilworth shopping centre.
Witnesses told police one man in his 20s stabbed another in his 50s in the neck in what appeared to be a random attack.
Others on the bus tried to save the victim by compressing the wound with clothing, but were unable to stop the bleeding.
The man was rushed to hospital but died from his injury. His name has not been released.
RCMP cordoned off the area but were unable to find the suspect. They are asking anyone with information to call them.