The St Louis Rams will relocate to Los Angeles following a vote of NFL owners.
The Rams had been vying with the San Diego Chargers and the Oakland Raiders for the chance to move to LA.
The Chargers could still join the Rams in the city, which has been without an NFL franchise for 21 years, but the Raiders face an uncertain future.
Rams owner Stan Kroenke called it a "bitter sweet" moment and said it had been the "most difficult process of my professional career".
Kroenke, who is also the majority shareholder at Premier League football club Arsenal, added: "Reaching two Super Bowls and winning one are things all St Louisans should always treasure."
NFL Commissioner Roger Goodell called relocation a "painful process" after owners voted 30-2 in favour of the Rams, who must pay the NFL a £311m ($550m) relocation fee.
The move has angered Rams fans and Missouri governor Jay Nixon.
He said the move set "a terrible precedent" not only for St Louis but for all communities that have "loyally supported" NFL franchises.
Nixon added that there would be a thorough review of the NFL's decision before determining what next steps to take.
The Rams have played in LA before, first moving there from Cleveland in 1946. They left for Anaheim in 1980, before moving to St Louis in 1995.
They are the only franchise to claim three NFL championships in three different cities, winning Super Bowl XXXIV in the 1999 season.
The Rams will play their home games at the LA Coliseum until their £1.29bn ($1.86bn) stadium in Inglewood is complete.
Should fans in St Louis want to continue supporting the Rams, they face a trip of around 1,800 miles.
That is a car drive of approximately 27 hours or a flight of about three-and-a-half hours in duration.
What's the reaction in St Louis?
NFL fans in the city have now lost two franchises after the Cardinals moved to Phoenix in 1988.
St Louis mayor Francis Slay said the NFL had "ignored" the loyalty of St Louis fans, who "supported the team through far more downs than ups".
He also said that the NFL had "ignored" the facts, a strong market and viable plan for a new £706m ($1.1bn) stadium on the river front.
"It is just a slap in the face for the city," said Rams fan Jermaine Chambers, who pointed the finger of blame at Kroenke.
"Even though things might not have gone the way he wanted them to, he created the relationship with the city so it is kind of his fault.
"Beyond that, he still made money here. To dump on the city, to dump on the people and the community I just think it was classless."
Why move to LA?
Los Angeles had been without an NFL franchise since the Raiders and Rams left the region in 1995.
The move is expected to bring greater revenue from naming rights, TV and future hosting of the Super Bowl.
But there are no guarantees that LA can ultimately support two NFL teams in a city saturated with sports and entertainment options.
The Los Angeles metropolitan area already has:
2 NBA teams: Lakers and Clippers;
2 NHL teams: Kings and Anaheim Ducks;
2 MLB teams: Dodgers and Los Angeles Angels of Anaheim;
And 1 MLS team: Galaxy (with Los Angeles FC starting in 2017).
What happens to the Raiders?
Oakland are uncertain which city they will call home in 2016 after the failure of their bid, according to owner Mark Davis.
The franchise's lease at Oakland Coliseum, where they have played since moving north from Los Angeles in 1995, has expired and the city has not expressed willingness to contribute public money for a new stadium.
"I don't know where we'll be," said Davis. "We're trying to figure that out. We made a commitment to try to get to Los Angeles."
Davis ruled out moving the Raiders to St Louis to fill the void left by the Rams, but said all other options would be considered, including a move to San Diego should the Chargers vacate the city.
"America, the world, is a possibility for the Raider nation," he said.