Police, ambulance crews and the Coastguard rushed to the Itchen Bridge just after 3pm on Friday.
They received reports that a man had fallen from the bridge into the water.
LIVE UPDATES: Coastguard helicopter over Itchen Bridge
Hampshire Constabulary has confirmed that the man has been pronounced dead and file will be prepared for the coroner.
A heavy police presence was visible in the area throughout Friday, with officers patrolling the riverside as well as blocking the eastbound lane of the bridge.
A Coastguard helicopter from Lee-on-the-Solent was also called, hovering over the bridge at around 3.15pm.
A spokesperson for Hampshire Constabulary said: “We were called at 3.10pm on 31/1 to reports of a man who had fallen from Itchen Bridge.
“We attended along with our colleagues from South Central Ambulance Service.
“The man has been pronounced deceased and a file is being prepared for the coroner.”
Police at the scene were keeping passers-by away from the cordon as they dealt with the incident.
One driver who came across the Itchen Bridge and parked on Albert Road South said they “couldn’t look away” from the cordon on the bridge.
“It’s one of those things you really don’t want to look at but can’t stop yourself, I couldn’t focus on the road.
“You couldn’t see anything from the road but my eyes kept going back to the [police] tape”
“I saw a helicopter at the bridge earlier,” said a Weston resident heading to work in the city centre.
“Police asked me to cross over to the other side of the pavement and then I realised something bad had happened. I didn’t want to ask questions but I’ve never seen so many police cars on this bridge before.”
Cyclist Lisa King is not from Southampton, being in the city to visit a family friend.
She said she “kept her head down as much as possible” while pedalling past the cordon, not wanting to look at the police tape.
While traffic moved smoothly past the lane closure, there was heavy queues around the city centre.
Central Bridge, Marsh Lane, Terminus Terrace and Platform Road were all badly affected.
