"It's historic not only that it's the first flight … but I also get to discover the country where I was born," he told the Palm Beach Post. "This is my first time going back home."
Santana's tip for those hoping to go to Cuba: If you have a Cuban passport, be sure to use that name when you book your flight.
Mark Gale, CEO and president of Fort Lauderdale-Hollywood International Airport, said he's proud of his team and JetBlue.
The airline accounts for about one-fifth of all flights at the airport.
"To have that very, very first flight come out of our airport is a great honor," he said.
Fort Lauderdale's airport is host to more weekly trips to Cuba than Miami, which Gale said is "a testament to the reputation of Fort Lauderdale."