The unnamed man, who is reported to be from London, collapsed on Grand Avenue in Hove just before midday, 16 miles into the race.
He was treated at the scene by paramedics and an off-duty police officer, then taken to the Royal Sussex County Hospital in Brighton where he died after emergency surgery.
It is the second time in recent memory that a young person has died during a marathon in England, with 30-year-old Claire Squires having suffered a heart attack one mile short of the finish at last year's London Marathon.
"It's tremendously sad. I can confirm that a competitor collapsed and later died in the Brighton marathon this morning,” race director Tim Hutchings said.
"We have rigorous emergency plans here in Brighton, much of the best practice we've taken from events as high calibre as the London marathon.
"Obviously this is dreadfully sad news for the entire Brighton marathon team and we pass our condolences on to all his family."
Over 9,000 people took part in the marathon on Sunday.