The St Louis Rams will play one of their regular season home games in the UK in each of the next three years.
They will take on the New England Patriots on 28 October in London.
In October the NFL said at least one competitive fixture would be held at Wembley every year until at least 2016, and there was speculation that London would get two games in 2012.
The Rams, who are owned by Arsenal's majority shareholder Stanley Kroenke, won Super Bowl XXXIV in 1999.
The league's commissioner, Roger Goodell, said: "The response to NFL games in the UK among our British fans has been exceptional.
"We are confident that having the Rams host one game in the UK in each of the next three seasons will allow us to better serve the growing popularity of our sport beyond the borders of the United States."
Kroenke said: "This is a tremendous honour for our franchise, the city of St Louis and our fans throughout the world. We are excited about the opportunity to reach new audiences globally. This is a great platform to showcase the city of St Louis to London and the UK.
"We've seen first hand the increased popularity of the NFL not only in London but throughout Europe. To play a role in that growth over the next three years will be incredible."
With the Patriots hosting Baltimore in the AFC Championship game on Sunday, fans at Wembley could easily end up seeing the defending Super Bowl champions in October.
New England are no strangers to London, having enjoyed an easy victory over the Tampa Bay Buccaneers in 2009.
Patriots chairman and chief executive Robert Kraft said: "The United Kingdom is home to some of our most passionate Patriots fans, including the UKPatriots, who are among our most active fan clubs overall, not just overseas. We look forward to another memorable experience."
The NFL's decision to invite teams to apply to play in the UK on an annual basis is part of a strategy which could ultimately lead to a franchise being based in Britain.
"When the initial resolution to play international regular-season games was approved in 2006, the thinking at the time was that we would have two new teams every year," said the NFL's Chris Parsons.
"As the series evolved, we saw that having a team return to the UK on a regular basis would increase fan interest for that particular team, which in turn would drive fan growth for the entire league.
"We are incredibly excited to introduce a young, talented team like the Rams to our UK fans. And to do so against a team with the rich history and tradition of the Patriots makes it even more exciting."
While the decision to bring a team back for repeat visits does mark the next step in the NFL's international expansion, their ambition of bringing a second game to the UK each year will not be realised immediately.
In October, John York, co-owner of the San Francisco 49ers and head of the NFL owners' international committee, said: "We will increase the number of games to at least two [per season] and to encourage at least one of the two games to have a team that comes back for a minimum of three and possibly as many as five years in a row."
He said this strategy was designed to persuade British fans not only to attend games in the UK, but to build up an affinity with one of the regular participants.
Asked whether the UK could one day have its own team, York said: "Obviously having a franchise here is a long-range plan.
"We'll have to see what we go through over the next few years, but if the game continues to grow and people love the game, the endgame of having a franchise in London would be terrific."
York would not be drawn over whether a UK team would be part of a wider NFL expansion, or involve an existing franchise leaving a US city for London.
Last year's game between Chicago and Tampa Bay failed to sell out, largely because the NFL's protracted labour dispute meant tickets could not be sold anywhere near as early as in the previous four seasons.
The decision to play three Rams games in London has not gone down well locally, the sports editor of the St Louis Post-Dispatch, Reid Laymance, said.
"So far, people are not happy. It's magnified in St Louis because there are concerns about [the fact that] the lease runs out in 2014 on the stadium."
And with the huge Los Angeles area being without a team, there has been speculation that the Rams franchise may relocate - either to the West Coast of the United States or to London.
"People are saying that Stan Kroenke is not committed [to staying in] St Louis," said Laymance.