Police are urgently appealing for witnesses, information or dashcam footage following the crash in Low Poppleton Lane, York, at around 5pm.
The crash involved the girl and a motorcycle, which left the scene.
The girl was rushed to Leeds General Infirmary with serious injuries.
A North Yorkshire Police spokesman said: "Police are urgently appealing for witnesses, information and dashcam or CCTV footage following a serious collision in York this afternoon.
"At about 5pm, police received a report of a serious collision on Low Poppleton Lane, York, involving a pedestrian - a 12-year-old girl - and a motorcycle which left the scene.
"The pedestrian suffered serious head injuries and was taken to Leeds General Infirmary for treatment.
"The motorcycle, believed to be grey or silver in colour, left in an unknown direction. The rider is described as wearing a black jacket and had a white helmet on.
"The scene is closed off and will remain so for several hours while Forensic Collision Investigators examine the scene. Motorists are asked to avoid the area.
"The girl's family are with her at this difficult time."
Anyone with information can call police on 101 quoting NYP-12062019-0335.