The NFL says it will play at least two games per year at Premier League club Tottenham's new stadium over a 10-year period.
Tottenham's new stadium is expected to open in the summer of 2018 and will feature a retractable grass field with an artificial surface underneath that would be used for NFL games.
Tottenham chairman Daniel Levy says: "We have an opportunity now to deliver one of the most unique sporting and entertainment venues in the world, bringing together the EPL and NFL for the first time."
The NFL currently has two years remaining on a deal with Wembley Stadium, where it has staged 11 regular-season games since 2007.
The NFL says it is "optimistic" the relationship with Wembley will be extended beyond 2016.
However, the NFL says games may also be played at different U.K. venues.