Tottenham Hotspur and the NFL have reached an agreement for at least two games a year to be played at the Premier League club's new stadium.
Tottenham received the green light to build a new stadium in the shadow of their current White Hart Lane home in North London in March.
It is expected to hold around 60,000 spectators and is due to open in 2018.
The club said on Wednesday that a 10-year partnership had been agreed with the NFL for American football games to be played at the new ground.
The Club & the @NFL have reached agreement for a minimum of two games per year to be played during a 10-year partnership at our new stadium.
- Tottenham Hotspur (@SpursOfficial) July 8, 2015
A statement appearing on both Tottenham's official website and the NFL UK website read: "The NFL and Tottenham Hotspur today announced that they have reached agreement for a minimum of two games per year to be played during a 10-year partnership at the English Premier League team's new stadium in London.
"The state-of-the-art stadium, due to open in the summer of 2018, will feature a retractable grass field with an artificial surface underneath that would be used for NFL games. This innovative field will add greater flexibility in the scheduling of games, with the NFL having its own playing surface for games held at this venue. This field will be multi-use and capable of hosting other sporting, entertainment and community events."
NFL games have already been staged successfully at Wembley in the English capital since 2007, and NFL commissioner Roger Goodell said: "With growing enthusiasm for the NFL in the United Kingdom, we are committed to hosting NFL games in world-class venues and are excited to partner with Tottenham Hotspur to play games at their future stadium.
"We share a vision and commitment to creating the best experience for our teams, fans and the local community."
The full story of our agreement with the @NFL can be found here - http://t.co/bFixyygQIo pic.twitter.com/tWMzpUf3vX
- Tottenham Hotspur (@SpursOfficial) July 8, 2015
Tottenham chairman Daniel Levy added: "We have an opportunity now to deliver one of the most unique sports, leisure and entertainment venues in the world, bringing together the EPL and NFL for the first time.
"The socioeconomic benefits this will bring to the area will be immense and demonstrates our commitment to the regeneration of this priority borough in London.
"We have always underlined the importance of public sector support for the long-term regeneration of the area. This support is now clearly in evidence in the master plans that have been brought forward by the London Borough of Haringey, both through the Northumberland Park project to the east of the stadium and the High Road West scheme.
"These plans, alongside the commitments made by the Mayor of London and the Greater London Authority to infrastructure and public realm investment, and with the support of Central Government, demonstrate that there is now a collective public and private sector desire to deliver lasting change to the area.
"This was an important factor for the NFL when they agreed to bring their hugely popular sport to Tottenham. I am delighted that we have succeeded in attracting them. We have a compelling and exciting partnership that will play its part as we begin transforming this area of Tottenham."
Mayor of London Boris Johnson also welcomed the news.
"Anyone who has seen American football at Wembley Stadium cannot fail to have been thrilled by the spectacle, and the wise heads that run the NFL have clearly not missed the fact that Londoners are going absolutely gangbusters for gridiron," Johnson said.
"We are already working very closely with the NFL, including on plans to get more Londoners involved in the sport, and we believe that building on the success of NFL at Wembley by staging more games in an area of the city that has been earmarked for a massive programme of economic regeneration and investment makes perfect sense.
"Touchdowns in Tottenham can only add to our reputation as a global sporting powerhouse, and help us take another step towards our goal of having a permanent NFL franchise here in London."