Emergency services responded shortly after 4.50pm on Wednesday to reports of an accident in Staniforth Road in the Darnall area of the city.
South Yorkshire Police said it is understood that a grey Audi drove towards three electric bikes, colliding with one rider.
The car continued to travel following the crash with the electric bike and was further involved in a collision with a teenage pedestrian.
The driver of the Audi failed to stop at the scene.
Graphic CCTV footage of the incident appears to show the car veer into the opposite carriageway before hitting the 16-year-old pedestrian at speed.
The boy was taken to hospital. Despite emergency treatment, he died as a result of his injuries. The boy’s family has been informed and are being supported by specialist officers.
An 18-year-old man, who was the rider of the electric bike, remains in hospital with serious injuries which are not thought to be life-threatening.
A 20-year-old man in Kent has been arrested on suspicion of murder. He remains in police custody.
Three people, a 45-year-old woman and two men aged 26 and 46, have been arrested on suspicion of assisting an offender. All three remain in custody.
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Senior Investigating Officer in the case, Detective Chief Inspector Benjamin Wood, said: “This is a tragic incident in which an entirely innocent bystander, who was going about his daily business, has sadly lost his life. Our thoughts are with the boy’s loved ones, and we remain focused on securing justice for them.
“We know that this incident will have caused concern in the local community, and we have a team of detectives working at pace to piece together the circumstances which unfolded.
“We’re aware of footage being shared online and I’d like to reiterate our message to the public to withhold from speculating or circulating videos which may cause distress to the boy’s family.
“If you have any footage, imagery or information that may help our investigation then please share this directly with us – it may form an important part of our enquiries. We are also keen to hear from the riders of two electric bikes who were in the area at the time of the incident.”
