North Yorkshire Police have launched a manhunt after the incident in the early hours of Wednesday morning.
Police say they were called to Gillygate in York at 5:45am to reports of an assault.
They found a man with serious injuries who was taken to York District Hospital.
The force has said it is 'unknown' how the man sustained the injuries, but they are searching for a man they believe was involved.
A spokesperson for North Yorkshire Police said: "We received a report at 5.45am of an assault on Gillygate, York.
"A man was taken to York District Hospital with serious injuries.
"It is unknown at this stage how the injuries happened.
"Enquiries are ongoing to locate a man believed to be involved in the incident.
"The road is currently closed until further notice."
The road is closed in both directions and motorists are being urged to avoid the area.
Gillygate links the A19 and the B1363 and its closure is expected to have a knock on affect in traffic on other roads in the area.
Police have told passers-by the road will be closed to traffic and pedestrians for most of the morning.
Gillygate is one of York's main roads for traffic and is lined with shops and cafes.