Taking place on the same day as the London Marathon, the city's own 26.2-mile challenge has attracted 10,000 participants and is the biggest running event in the city's history.
Runners set off from Palmerston Park at 09:00 BST, passing The Bargate and the QE2 Anchor, going through St Mary's Stadium, and finishing at the Guildhall Square.
Road closures have been put in place.
The route covers the Cobden, Northam and Itchen bridges.
Other events include a half marathon, a 10km race, and a family fun run.
Former Southampton footballer Matt Le Tissier, who took part, called it "good fun".
"The people of Southampton turned out and gave us some great support," he said.
Roger Bradley, 73, from the Lordshill Road Runners Club, was the oldest person taking part.
"It's not because I feel the need to exercise," he said.
"I'm just as happy in a pub with a pint of beer and a packet of crisps."
Georgia Edwards ran in memory of her autistic brother Joseph who took his own life.
She said: "I found it really difficult to speak about it, we all have our own ways of dealing with loss, so for me, now, I needed a challenge in my life.
"This is my way of showing my brother that I'm doing something for him."
Chris Rees, race director, called it their "biggest and most ambitious" event, and a "huge spectacle".
More than 30,000 people have descended on Southampton for the event, with 850 volunteers involved.
The city's last full marathon was in 1984.
Southampton has hosted its first full marathon in more than 30 years.