Thomas Cook Airlines will fly direct from Manchester to San Francisco from May 2017.
The new route joins flights to Los Angeles and Boston launched in 2016, and New York and Miami in 2015.
In addition to the new route, flights to Los Angeles will also increase from two to three flights per week, with Boston jumping from two to four flights per week.
Customers can also connect to around 90 North American and Caribbean cities, thanks to agreements with partner carriers.
Thomas Cook’s Chief Airlines Officer, Christoph Debus, said: “It’s never been so easy for our customers to reach top US destinations.
“With seven direct US routes from Manchester, five of which we have launched in the last three years, we’re making good progress with our strategy to grow our long-haul network.”
“It’s also great news for the north of England as not only can passengers reach the stunning scenery of northern California direct, they are also connected with the booming business hub of Silicon Valley.”
Thomas Cook has seen a surge in flights and holidays to the USA.
Passenger numbers to the US on Thomas Cook’s UK airline have more than trebled in the last two years, and almost one million Thomas Cook customers will have flown Stateside from across Europe during this year’s winter and summer seasons – an increase of 40% year-on-year.
Ken O’Toole, CEO of Manchester Airport, said: “We are pleased that Thomas Cook Airlines continues to grow from Manchester Airport and look forward to working closely with them in future as they expand further.
“The addition of a new San Francisco service and increased frequency on the existing Los Angeles and Boston routes means there will be more than 2.2m seats on sale between Manchester and the States in the coming year.
“That represents growth of more than 25% over two years, with more seats added at Manchester than at any of the other top 25 airports in Europe, cementing our position as the global gateway for the north.”
Thomas Cook Airlines is also launching London Gatwick-Cape Town flights in December 2016, while sister airline, Condor, has also expanded its direct flight to the US from Germany in the last two years to include Austin, Portland, New Orleans and San Diego.
Direct flights to San Francisco from Manchester Airport start on May 14, 2017 with departures on from Manchester on Thursdays and Sunday.