Cubans saluted the packed American Airlines flight by spraying water from firetrucks above the plane as it taxed along the runway at Jose Marti International Airport in honor of the inaugural voyage.
"It was very emotional for me," said Jonathan Gonzalez, 31, a Cuban-American born in Miami who said it was his third time visiting the island.
Passengers wearing straw hats provided by American Airlines with the word "Cuba" on the back were greeted with welcome signs in various languages but no music.
"I'm intrigued to see how the city is after the death of Fidel Castro," said Tamara Cara, 45, an education professional from Puerto Rico on the flight.
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For years US travelers to the island have had to go through burdensome charter flights with four-hour check ins.
The US and Cuba signed a deal in February to restore commercial air traffic, marking one of the most important developments since Presidents Raul Castro and Barack Obama announced they would restore diplomatic relations nearly two years ago.
Several other flights from the US also were scheduled to arrive today.
American Airlines held a small celebration for the passengers in Miami before departing, serving typical Cuban staples like croquettes and cheese-filled pastries.
Gonzalez said he felt he was arriving at what will be a "difficult time" for the island but remained optimistic for the country's future.
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