JetBlue Flight 387 took off at 10:06 a.m. local time from Fort Lauderdale, Florida, with tourists, journalists and US authorities, including Transportation Secretary Anthony Foxx, on board, an event broadcast live by US English and Spanish-language media.
The 220-seat Airbus A320's arrival in Cuba marks a new milestone in the diplomatic thaw between the former Cold War enemies, which in December 2014 announced the start of the process of normalising relations.
Foxx told members of the media, including EFE, on board the plane that the flight was a tangible example of the Obama administration's efforts to mend decades of animosity.
The plane landed in Santa Clara ahead of schedule despite a 20-minute delay in Fort Lauderdale and, just as occurred at take-off, was greeted with a ceremonial water cannon salute.
Foxx was the first person off the aircraft and was welcomed at the bottom of the steps by Cuba's Deputy Transportation Minister, Eduardo Rodriguez.
The US official is scheduled to board a second flight for Havana, where he will meet Cuba's Foreign Minister Bruno Rodriguez, and Transportation Minister Adel Yzquierdo.
Cuba's Ambassador to the US, Jose Ramon Caba?as, said after taking part in a ribbon-cutting ceremony with JetBlue CEO Robin Hayes amid a festive atmosphere at the Fort Lauderdale-Hollywood International Airport that the resumption of commercial flights between the two countries was "historic".
He recalled in his remarks to reporters that the bilateral agreement was signed just months ago -- in February -- but that all sides involved had worked efficiently to make the flights a reality, adding that they would "benefit everyone".
Mirtha Rodriguez, a Cuban woman who has settled in the United States and was one of the 150 passengers on board the flight, told EFE prior to take-off that neither she nor her family wanted to miss this historic occasion.
Like other passengers, she had travelled to Cuba on charter flights but said the commercial service was cheaper and also more convenient because of the option of making reservations online.
Wednesday's direct flight to Cuba was the first of 110 daily round-trip flights authorised in 2016 by the US Department of Transportation, which also gave American Airlines, Frontier Airlines, Silver Airways, Southwest Airlines and Sun Country Airlines permission to provide service to nine cities on the Communist-ruled island.
No flights to Havana were authorised because the amount of requests exceeded the number of slots agreed by the two governments.
American citizens may travel to Cuba if their trip falls under one of the 12 US government-authorised categories, including family visits and those related to cultural, journalistic and professional activities.
But tourist visits to the Caribbean island by American citizens are still prohibited under the 54-year-old US economic embargo on the island, which only Congress can lift.
