A dramatic finish saw the Jacksonville Jaguars beat the Buffalo Bills in front of over 84,000 fans at Wembley.
The Bills came from behind with 28 unanswered points to lead with two minutes remaining but Allen Hurns' diving touchdown sealed a 34-31 win.
His score - with little room to work with in the corner - sealed the Jags' first Wembley win in three attempts.
Marcus Easley and Corey Graham scores set the Bills up for a win on their London debut before the late drama.
Pre-game favourites the Bills will rue early errors from quarterback EJ Manuel who fumbled to allow Chris Clemons a score and then saw a pass intercepted by Telvin Smith, who touched down in the second quarter.
Seeking just their second win of the regular season, the Jaguars looked edgy despite their 27-13 half-time lead and Graham ran home a 44-yard interception to give the Bills a late advantage, sparking wild scenes on their bench.
But quarterback Blake Bortles was given time to throw a 31-yard pass to the corner and Hurns dived athletically to land inches inside the end zone.
"I just tracked the ball, it was in the moment," Hurns told BBC Sport. "I had to dive for it but you've got to lay it on the line."
NFL UK fever
The crowd of 84,021 is the second highest in the 13 games since Wembley began staging International Series matches in 2007.
The occasion also sparked activity on social media, with #NFLUK trending in the UK and the subject of over 10,000 tweets from midday.
Plenty more NFL to come in the UK
Fans of gridiron have not got long to wait for the next Wembley instalment as the Detroit Lions meet the Kansas City Chiefs at the home of English football next Sunday.
And games in the UK will continue for the long term, as the NFL has extended its deal to stage at least two a season at Wembley until 2020, while another agreement has been signed for two matches a year at Tottenham Hotspur's new stadium from 2018.
A minimum of four fixtures a year in London is seen as a long-term precursor to a franchise from sport's richest league being based permanently in the English capital.