The man, aged in his 30s, was struck by a black Audi A3 on Halifax Road, close to the turn for Sainsbury's, Hillsborough.
South Yorkshire Police said emergency services were alerted to the collision at 6.10am and the pedestrian was rushed to hospital with 'potentially life threatening injuries'.
He has reportedly undergone surgery.
The windscreen of the car involved in the collision was shattered during the incident.
Road traffic collision investigators have examined the vehicle.
Halifax Road has been cordoned off while investigations at the scene continue.
Buses and motorists have been diverted away from the road, leading to delays in the area.
A South Yorkshire Police spokesman said: "Emergency services were called to Halifax Road, Sheffield, just after 6.10am this morning, following reports of a collision.
"A black Audi A3 was involved in a collision with a pedestrian, close to the turning for Sainsbury’s.
"The pedestrian, a man in his 30s, has been taken to hospital with potentially life-threatening injuries."
Witnesses should call South Yorkshire Police on 101.