Quarterback Blake Bortles threw for two touchdowns and rushed for another as the Jacksonville Jaguars beat the Indianapolis Colts 30-27 at Wembley.
The Jaguars led 23-6 after the third quarter before a Colts comeback.
Indianapolis scored three fourth-quarter touchdowns, but Allen Hurns' 42-yard touchdown catch from Bortles with just over two minutes left ensured Jacksonville's victory.
It was the Jaguars' second win in their fourth NFL appearance at Wembley.
Jacksonville, the designated home team, had lost their first three games of the NFL regular season but looked good for a 17-6 half-time lead, after Allen Robinson touched down in the first quarter and Bortles ran through to score in the second.
The Colts were playing their first overseas NFL game, and only woke up in the final quarter.
Frank Gore rushed for a touchdown and quarterback Andrew Luck threw a two-yard pass to TY Hilton, who made it a three-point game with five minutes left.
However, Hurns collected a pass from Bortles and expertly weaved past several players for a touchdown that meant Phillip Dorsett's 64-yard score for the Colts with three minutes on the clock was in vain.
What they said
Jacksonville Jaguars quarterback Blake Bortles told BBC Sport: "The guys played their tails off. It was fun and cool to see, and it was good to get back on track.
"It definitely feels good to come here and win over here as well."
Indianapolis Colts' quarterback Andrew Luck said on www.colts.com: "They played better than us. We didn't play better in the first half. We didn't play particularly better in the second half.
"We made enough plays to almost get them, but almost doesn't cut it in this league. We've got to be better, I've got to be better. It's pretty simple."
More than 83,000 attended NFL's latest Wembley game, and they were treated to a pre-match performance by singer Robin Thicke.
Wembley Way outside the stadium, normally filled with football fans on cup final and play-off match days, was taken over by NFL supporters, some wearing jaguar masks and others with horseshoes painted on their faces.
Both sets of players were given a guard of honour on to the field by members of the armed forces holding the national flags of the United Kingdom and the United States.
There were plenty of sporting celebrities in attendance, including Great Britain's Olympic women's gold-medal winning hockey team.
One of the defining images of this NFL season has been San Francisco 49ers' quarterback Colin Kaepernick kneeling during the United States national anthem in recent months, in protest against what he called the oppression of black people in his country.
Several sportspople - both within and outside the NFL - have joined him in support and on Sunday, the Colts cornerback Antonio Cromartie knelt on one knee and raised his right fist as well.
Cromartie later stood up for UK anthem God Save the Queen.
Some fans at Wembley on Sunday were also seen wearing Kaepernick jerseys - the replica kit became one of the top-selling in the days after his stance gained widespread attention.
The Jaguars' win on Sunday made it back-to-back victories at Wembley, after their win over the Buffalo Bills 34-31 in 2015. Jacksonville's first two visits to London had ended in defeats.
London will host two more games this season, with the New York Giants and the Los Angeles Rams playing at Twickenham on 23 October, before the Washington Redskins take on the Cincinnati Bengals at Wembley on 30 October.
The NFL's international series in the regular season first took place in 2005 in Mexico, which will also play host to a game this year - the Houston Texans versus the Oakland Raiders on 21 November.
Wembley will be used as as one of the overseas venues until 2020 after the deal was extended last year.