The 48-year-old pedestrian was struck by a black 4x4 in Cottenham Road, St Ann's, at about 10.15pm last night.
South Yorkshire Police said the vehicle was driving towards the junction with Doncaster Road at the time of the collision.
A police spokeswoman said: "The pedestrian, a 48-year-old man, was taken to hospital with serious and potentially life-threatening injuries. He currently remains in hospital receiving treatment for his injuries.
"Officers are asking for anyone who saw what happened, or who has any information as to the identity of the driver or the vehicle involved, to contact them.
"Did you see what happened? If you have any information, or saw the 4x4 prior to the incident, please call."
Ring South Yorkshire Police on 101 or Crimestoppers on 0800 555 111.