South Yorkshire Police said the teenager was discovered by a member of the public on Holgate Avenue, Parson Cross, at 12.30am today.
He was taken to the Northern General Hospital by ambulance but died of his injuries about an hour later, a police spokeswoman said.
Police would not comment on reports he had been stabbed.
Detectives believe the man, who has not yet been formally identified, may have attended a function at the White Horse pub on Halifax Road on Friday evening before leaving at 11pm.
The victim is thought to have been making his way home towards the Ecclesfield area when he was allegedly attacked.
Police have arrested two men and a juvenile on suspicion of murder. They are being held at police stations in Sheffield, the spokeswoman added.
A forensic post-mortem examination is taking place to establish the cause of death.
Anyone with any information is asked to contact the incident room at Moss Way police station on 0114 2202020 or call Crimestoppers anonymously on 0800 555111.