The airport welcomed the return of services to a number of transatlantic destinations after the Biden administration confirmed its borders would reopen to fully vaccinated Brits.
The first stateside-bound flights from Manchester were Virgin Atlantic services to Orlando and New York, with Orlando being the first departure.
The Orlando service departed at 10.10am and the New York flight left at 1.10pm. Routes to Atlanta and Houston are also set to return over the coming weeks and months.
This includes the launch of routes by Aer Lingus, with the Irish carrier opening a new base in the north of England for the first time, which will reportedly create 153 jobs.
Karen Smart, managing director of Manchester Airport, said the US routes were "vital" to the northern economy and the "prosperity" of the region.
"After almost two years with no flights to the USA, it is great to finally re-connect the region with some of our most popular and important destinations," she added.
"I look forward to working closely with our airline partners as more services come back to Manchester, plus I would encourage businesses and other organisations with links to the US to get in touch so we can help them unlock their potential through our international reach."
Virgin will operate a six-times a week service to New York using an Airbus A330, with return fares from £532pp. Aer Lingus will also offer flights to the city from 1 December with fares from £179pp each way.
The Irish carrier also offers return fares to Orlando from £209pp each way, as does Virgin from £587pp.
Virgin is also set to resume flights to Atlanta from 2 December, with prices starting at £836pp.
Singapore Airlines’ three-times weekly service to Houston will return to the airport from 1 December. Return fares start at £479pp.
Juha Jarvinen, chief commercial officer at Virgin Atlantic, said the airline "can’t wait" to fly customers to the US.
"These three routes provide an array of US holiday options, from family fun and thrills at Orlando’s theme parks, to the exhilarating and vibrant atmosphere in the Big Apple, to the best of the South in Atlanta, soaking in the history and culture," he added.
Reid Moody, chief strategy and planning officer at Aer Lingus, welcomed the move, describing it as "very meaningful" to passengers with connections in the US.
"We know there is strong demand for direct transatlantic services from the north of England to North America and we’re excited to see travellers and holidaymakers enjoying the welcoming Aer Lingus experience that we’re known for," he added.
Mohamed Rafi Mar, Singapore Airlines’ UK and Ireland general manager, said: "Before the Covid-19 pandemic, which forced 98% of our flights globally to be grounded in March 2020, Singapore Airlines had been Manchester Airport’s longest serving long-haul carrier, having operated continuously since 1986."
