Delta Air Lines is buying Singapore Airlines' 49 per cent stake in Virgin Atlantic for $360 million (£224m).
Under the joint venture announced this week, Delta and Virgin would share costs and revenues on routes between Britain and North America.
The pair plan to cooperate on services between New York and London, with a total of nine daily round-trip flights from London Heathrow to John F. Kennedy International Airport in New York and Newark Liberty International Airport in New Jersey.
Delta, the second-largest U.S. airline by revenue after United Continental, has acquired stakes in Grupo Aeromexico and Brazil's Gol Linhas Aereas over the past year, and has long hoped to break into Heathrow.
In recent years, it has invested heavily to build a major hub in New York.
The tie-up with Delta will be a shot in the arm for Virgin Atlantic, which is the second-largest carrier at Heathrow after IAG's British Airways. It has been battered by rising fuel prices and the euro zone crisis.
It lost £80 million in its last full year.
The Virgin Atlantic partnership will "provide a more effective competitor between North America and the U.K., particularly on the New York-London route, which is the largest airline route between the U.S. and Europe," Delta Chief Executive Richard Anderson said in a statement.
The airlines said they would file an application with the U.S. Department of Transportation for competition clearance and said the deal would need to be reviewed by the U.S. Department of Justice and the European Union's competition regulator.
The deal will give Delta greater access at London's Heathrow, a lucrative hub for corporate passengers where landing slots are generally hard to acquire.
Heathrow, Europe's busiest airport, is operating at close to full capacity after the UK government blocked its expansion in 2010.
British entrepreneur Richard Branson said he would retain his 51 per cent stake in Virgin Atlantic and maintain the brand of the airline he founded in 1984.
"The partnership allows both carriers to offer a greatly expanded network at Heathrow and to overcome slot constraints, which have limited the growth and competitive capability of both airlines," Branson said.
The two carriers will operate a total of 31 peak-day round-trip flights between Britain and North America, 23 of which operate at London Heathrow.
The partnership will be similar to that operated by American Airlines and BA since 2010 on transatlantic and some European routes.
Singapore Airlines bought 49 per cent of Virgin Atlantic for $965 million in 1999, but has been open to selling its stake since at least mid-2011.
Singapore Airlines has been refocusing on its key markets where it is under pressure from budget airlines, launching its own budget carrier, Scoot, to ply Asian middle-distance routes and bolstering its Asian regional carrier, SilkAir.