The American Football League has held a regular season game in the UK since 2007.
Roger Maslin, managing director at Wembley Stadium, said the deal "cements" the partnership between the two organisations.
"We are delighted that the success of previous NFL events, combined with our commitment to making improvement year on year, has given the NFL the confidence to expand their presence at Wembley for the next five years. We look forward to being the home away from home for the NFL for many years to come," he said.
For the next three years the stadium will be home to the St Louis Rams, who have agreed to play a regular season game in the UK until 2014.
Their first game will be against the New England Patriots on 28 October.
Roger Goodell, NFL commissioner, said he is confident the deal will allow the NFL to "better serve" its growing popularity beyond the borders of the US.
"The response to NFL games in the UK among our British fans has been exceptional," he said.
The NFL is thought to have a current UK fan base of 11 million, with television ratings of games up 154% since 2006.
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