The New England Patriots and Tampa Bay Buccaneers will play in the third competitive NFL game at Wembley next year.
New England, who have won three of the last seven Super Bowls, will face 2003 champions Tampa Bay on October 25.
It is a huge boost for Wembley to secure the fixture after Murrayfield and Cardiff's Millennium Stadium showed an interest in staging the event.
NFL UK boss Alistair Kirkwood said: "We are very excited at the prospect of welcoming two of the leading teams.
"Both the Buccaneers and Patriots have strong fan bases here and are names that will be familiar even to those who don't follow the sport closely."
In October New Orleans Saints beat the San Diego Chargers in front of more than 80,000 fans at the stadium.