Nyad played "Reveille" on a bugle, thanked several dozen well-wishers who came to see her, then jumped feet first into the sea.
She swam away just before sunset, escorted by kayaks and several larger boats carrying her support team.
Earlier in the day, Nyad said it has been a lifelong dream and she hopes her feat, if successful, will inspire people to live vigorously during their golden years.
"I also want it to be a moment for thousands, and I dare say millions of people my age, who are going to look and say, '60!"' Nyad said at a news conference.
"The joke is 60 is the new 40, and it's true. We are a younger generation than the 60 that went before us."
She called the attempt a "symbolic moment" for increasing understanding between the United States and Cuba, two nations torn by five decades of animosity and mistrust.
"I'm under no delusion that my swim is going to make any new political ramifications," she added.
"But it is a human moment between the two countries."
Nyad spent the day eating, hydrating and meeting with members of her team. Five boats planned to sail alongside with 45 support crew on board, from navigators, nutritionists and doctors to shark wranglers and a film crew that has been documenting her story.
"I can't do this alone," she said at a news conference.
Nyad first had a go at this crossing as a 28-year-old back in 1978, when she swam inside a steel shark cage for about 42 hours before sea currents hammering her off course put an end to that attempt.
The following year she set a world record for open-water swimming without a shark cage, charting 165 kilometres from the Bahamas to Florida before retiring from competitive endurance swimming.
Still, she said the aborted Cuba attempt stuck with her all these years, and upon turning 60, she started thinking about a comeback.
"What if I went back and tried to chase that elusive dream of Cuba?" she said.
"And I started training and I found it was in my heart and it was in my body. ... It seems almost like a dream to me, but now it's real."
Australian swimmer Susie Maroney successfully swam the shark-filled waters from Cuba through the Straits and to the Keys in 1997, though she used a cage.
Nyad will be relying on special equipment that surrounds her with an electric current imperceptible to humans but strong enough to keep most sharks at bay. Whitetip sharks are not deterred by the field, so divers will be standing by to gently discourage any of those who get curious without harming them.
For the record to be considered valid, Nyad will have to make the swim without a wetsuit.
Her crew will navigate, monitor her health and provide nourishment.
But she is not allowed to touch the boat, nor can her helpers hold her, until she emerges fully onto dry land. Even that could be a challenge in Florida's mangrove thickets, exhausted and with no land legs after 2 days of swimming.
Nyad plans to swim a northwest course aiming to arrive at a point in the Keys a little east of due north, compensating for sea currents.
She plans to stop every 45 minutes for 20-second hydration breaks water, juice, sports drinks. Every 90 minutes she'll rest for 2 minutes and nibble on bread or a spoonful of peanut butter.
By day two she'll begin drinking heated water and hot chocolate to ward off hypothermia, which becomes a threat after so many hours at sea even with water temperatures expected to be 86 to 88 degrees Fahrenheit (30 to 31 degrees Celsius).
She described long swims as marathons of "sensory deprivation," unable to see or hear much through her fogged-up goggles and swim cap. Her thoughts will wander to abstracts like the nature of the universe, infinity, space and time.
At other times, songs run obsessively through her mind including "Guantanamera," the only Spanish-language tune she knows.
"I decide, OK, I'm going to sing 'Guantanamera' 2,000 times and that'll take me exactly three hours and fifty minutes," she said. "I try to pick songs that match my stroke. ... It just helps me pass the time."
Nyad said her un-retirement is a one-time thing, and after this she'll be hanging up her goggles.
"I didn't come back to be a marathon swimmer again. This is the only one," she said. "I just came back for Cuba."
-AP
