The 16-year-old was killed at around 7.30am today as commuters made their way to work in Birmingham.
Detectives launched a murder investigation as officers broke the news to the family of victim, who has yet to be formally identified.
The area was cordoned off and officers remained at the scene on Hagley Road.
The street, leading out of the city, was closed in the wake of the stabbing and was expected to stay shut for the rest of the day.
A suspect was detained in connection with the stabbing but later released, West Midlands Police said.
Police said a hunt has been launched for a man in his late teens or early 20s.
A police spokesman said: "At 7.37am today police received a call from a member of the public reporting that a passenger had been attacked.
"Officers and other emergency services were immediately dispatched but it was clear that nothing could be done to save the victim.
"West Midlands Police have identified the victim's family and are in the process of breaking the sad news."
West Midlands Ambulance Service said it was called to an emergency on board a bus in Edgbaston shortly after 7.35am.
A spokesman said: "A senior paramedic officer in a rapid response vehicle, two Basics (British Association for Immediate Care) emergency medics and two ambulance crews attended. One person was confirmed dead at the scene."
It is unclear where the girl was sitting when she was attacked on the crowded double-decker bus.
National Express West Midlands said the vehicle was heading out of the city when the stabbing happened.
A spokesman said: "We can confirm that a tragic incident occurred on a number 9 service this morning. Our thoughts and condolences are with the friends and family of the person involved and we will offer all possible support to the police in their investigation."
Shocked commuters took to Facebook to speak of their horror at the incident.
Darren Bent, from Birmingham, said his wife was on the bus. He wrote: "Can't believe some guy has just stabbed and killed a school girl right in front of my missus on the number nine bus on her way to work and she had to give CPR."
