The Key West, Fla., native began her fifth attempt to swim from Havana to the Florida Keys about 9 a.m. Saturday local time, trying to become the first person to do so without a shark cage, flippers or wet suit, CNN reported.
If all goes right, she said, the crossing should take about three days.
"There's the fine line between seeing that things are bigger than you and letting your ego go," Nyad said Friday during a news conference in Havana. "And there's another edge over that fine line where you don't ever want to give up and I am still at that place."
Nyad, who started her quest 35 years ago, said during the news conference she hoped her repeated efforts to swim between Cuba and the United States will help improve relations between the two countries. After her last attempt, Cuban officials said they received numerous suggestions about how Nyad could protect herself from stinging jellyfish that ended her previous attempts, CNN reported.
Nyad said she would wear surgical gloves and a specially designed face mask to prevent the jellyfish from stinging her.
"It took us a year" to develop the mask, Nyad said, explaining it was the type used to protect people who have face injuries.
"It's a two-edged sword for me," she said. "It's cumbersome, it's difficult to swim with, but it doesn't matter. I am safe. There's no other way."
Nyad is being accompanied by a 35-member crew who is monitoring her health, updating her progress on social media and trying to discourage sharks.
In 1997, Australian endurance swimmer Susie Maroney, then 22, completed the swim inside a shark cage, which she said not only provided protection from the predators but also helped protect her against waves and weather hazards.