The Rugby Football Union (RFU) has agreed a deal which will see at least three NFL games per season staged at Twickenham from next year.
Wembley hosted the first competitive NFL game to be played outside the Americas in 2007 and has continued to do so since then.
It was revealed on Tuesday that NFL stars will also showcase their talents at the home of English rugby union - the venue for the Rugby World Cup final between New Zealand and Australia on Saturday - from October next year.
The RFU have reached an agreement for games to be played at the south-west London stadium over a three-year period, with the opportunity for a further two games to be played at Twickenham during that time.
NFL executive vice president of international Mark Waller said: "We are committed to continuing to grow our sport in the UK and believe that adding Twickenham Stadium to our roster of host venues in London is further evidence of that commitment.
"We are very excited to give our fans the opportunity to enjoy NFL action at another world-class venue famous for attracting loyal and passionate fans from across the globe."
RFU chief commercial and marketing officer Sophie Goldschmidt said: "We are delighted to welcome the NFL to Twickenham, a stadium that has played such an integral role in what has been the biggest Rugby World Cup ever.
"The NFL has a strong and growing fan base in the UK, and this, combined with the investments we've made in our stadium will give fans more opportunities to experience the action first-hand at a world-class venue. We look forward to working with the NFL on this partnership."
The NFL last month agreed a deal for more games to be played at Wembley until 2020, while Premier League club Tottenham will host NFL games in their new stadium from 2018.