The incident happened on Shooters Hill Road near Maze Hill at around 4.15am this morning (February 24).
Officers and London Ambulance Service crews attended and found a man in his 40s injured.
He was taken to hospital for treatment with injuries thought to be life-threatening.
No other vehicles were involved in the incident.
Shooters Hill Road remains closed both ways between Charlton Way and Stratheden Road.
A Metropolitan Police spokesperson said: “Police were called to a collision involving a moped in Shooters Hill, SE10 around 04:15hrs on Monday 24 February.
“Officers attended alongside the London Ambulance Service and London’s Air Ambulance.
“One man in his 40s was taken to hospital where his injuries are thought to be life-threatening. No other vehicle was involved.
“Shooters Hill Road between the junctions of Charlton Way and Stratheden Road remains closed while enquiries continue.
“Anyone with information, including dash camera footage which may have captured the incident is asked to call 111 quoting the reference 712/24FEB.”
