Emergency services were called just after 12:30 BST to reports swimmers were in difficulty in the water.
Officers performed CPR on two men before paramedics arrived on the scene, Sussex Police said.
Both were then flown by helicopter to hospital where they remain in a serious but stable condition.
Three lifeboats joined coastguard helicopters to search for the missing man, but the RNLI stood its rescue crews down at about 16:20 BST.
Insp Mark Evans said: "We are working to establish who these two men are and trace their family and friends.
"We are continuing to support the search for the 19-year-old man from London who who is still missing.
"It seems this has been three people who have got into trouble while swimming with the changing tides and coastline."
Elizabeth Howarth was by the sea at the time. She tweeted: "We were on the beach just before it happened. Kids in the sea, no red flags. Hard to believe."
She said she saw one man being resuscitated on the beach, adding: "They were working on him for so long. It looked bad."
A 19-year-old man is missing and two other men have been airlifted to hospital after being pulled from the sea on the East Sussex coast.