Less than a week before she turns 63 years old, the Los Angeles woman is attempting a feat that even the fittest of human beings would find daunting. It's a dream that has taken three years of marathon open-water training swims and multiple aborted attempts at the crossing.
In the summer of 2010, unfavorable weather kept her from even setting out. Last year, first a debilitating asthma attack and then painful, dangerous stings from box jellyfish forced her from the water on two separate attempts.
This time Nyad is banking on a custom-made swimsuit to protect her from the jellyfish. It covers her head-to-toe with a pantyhose face and holes only for the eyes, nose and mouth.
It's non-buoyant but still creates drag in the water, so she hopes to don it only at night when jellyfish are more likely to rise to the surface.
"You have to learn from your mistakes. You don't do it the first time," Nyad said at a news conference, deeply tanned with goggle-rings around her eyes. "We need some luck, but we do feel like we've solved all the problems."
On her second try last summer, Nyad lasted 41 hours before calling it quits. She estimated it will take at least 60 hours to complete the swim to the Keys, and said the Straits of Florida were forecast to remain calm in the coming days.
Go-time had been planned for Sunday around dawn, but shifting weather forecasts prompted a last-minute change. The water north of Havana was slightly choppy Saturday, but expected to quiet down.
"This isn't perfect. You can go out and see some little whitecaps," Nyad said. "But I feel strong in the beginning, so why not get a few hours out and tonight it's going to calm."
In June, Australian endurance swimmer Penny Palfrey made it 79 miles of the way before throwing in the towel in the face of strong currents.
A fiercely driven competitor, Nyad acknowledged it was hard to watch Palfrey come close to snatching away her long-held goal.
"If she had succeeded I would have congratulated her, because I know how difficult it is, more than anybody. And after all, this is not my ocean," Nyad said. "But it is my dream. ... Frankly how can I lie? I'm glad that I still have the chance to be first."
Nyad first tried to cross the Straits of Florida in 1978 as a 28-year-old, but fell short.
For that attempt Nyad swam inside a steel cage, which she said not only protects from sharks and softens the waves but even creates a current that propels a swimmer forward.
On her third bid at a cageless swim, a 50-person support team including navigators, weather gurus and a shark handler from Australia were accompanying Nyad on five vessels. She planned to take short, periodic breaks for rest and nourishment.
In lieu of a cage, a kayaker will paddle alongside dangling an apparatus in the water that creates an electrical field designed to repel sharks. A team of shark handlers will carefully scan the surrounding waters from the roof of her main support boat, ready to dive in and gently nudge away any predators that make it through the shield.
Nyad confessed to sleeping poorly the night before and to feeling nerves, in addition to confidence, as she set out: "My heart is going to beat fast because this is history in front of me."
After falling short in the past she has vowed not to try again, but each time the siren call of the Straits proved too great.
Asked whether she would make another attempt if the weather, currents and marine life all cooperate but she is physically not up to the task, Nyad did not categorically rule out a fourth try.
But she suggested that even she has a limit.
"Sitting here, I can't address that," Nyad said. "I have to say, it's too much. I've asked too many people to put in too much. We know what we're doing. This has to be it. It just has to be."
Nyad set a world mark for open-water swimming without a wetsuit in 1979 by crossing 102 miles from the Bahamas to Florida.
A writer, journalist and motivational speaker, she said she hopes to inspire people of all ages to live active lives.
"Instead of staying on the couch for a lifetime and letting this precious time go by, why not be bold?" she said. "Be fiercely bold, and go out and chase your dreams."