The incident happened onboard a 472 bus in Woolwich Church Road just before 2.30pm today (January 7).
Officers and London Ambulance Service crews attended and found a boy who had been stabbed.
He was treated at the scene by paramedics, however, he was pronounced dead shortly after.
Police cordons and road closures remain in place whilst emergency services carry out enquiries.
No arrests have been made as police enquiries continue.
If anyone witnessed the incident or has any information which may help, they are urged to call police on 101 with ref 3795/07JAN25 or call Crimestoppers anonymously.
A spokesperson for Metropolitan Police said: “An investigation has been launched after the fatal stabbing of a teenage boy on a bus this afternoon.
“Police were called at 14:28hrs on Tuesday, 7 January to reports of a stabbing on a bus in Woolwich, SE18.
“The incident occurred on a Route 472 bus on Woolwich Church Road near the junction with the A205 South Circular Road.
“Officers attended, along with London Ambulance Service and London’s Air Ambulance.
“Paramedics treated a 14-year-old boy at the scene who had received stab wound injuries, but he very sadly died shortly after medics arrived.
“Police cordons and road closures remain in place whilst emergency services carry out enquiries. No arrests have been made at this early stage.
“If anyone witnessed the incident or has any information which may help, they are urged to call police on 101 with ref 3795/07JAN25 or call Crimestoppers anonymously.”