The New England Patriots suffered their second defeat of the season as the Carolina Panthers pulled off a thrilling NFL victory, while the New Orleans Saints were victorious in Wembley.
Inspired by quarterback Cam Newton, who hit form after a difficult start to the season, the Panthers held off a late rally from the reigning Super Bowl champions to win 33-30.
Newton raised a clenched fist after scoring a touchdown, joining several other players across the NFL in evoking Tommie Smith and John Carlos' Black Power salute as the controversial protests against racial inequality continued.
Newton was also involved in the play that led to Graham Gano's game-winning 48-yard field goal.
The Patriots have conceded more points than any other team in the league after four games.
The Atlanta Falcons suffered their first defeat of the season, losing 23-17 to the Buffalo Bills.
The Falcons were hampered by injuries to wide receivers Julio Jones and Mohamed Sanu, who both missed the entire second half, while two long field goals from Stephen Hauschka in the fourth quarter proved crucial for the Bills.
In the clash of the winless Ohio teams, the Cincinnati Bengals comprehensively beat the Cleveland Browns 31-7.
Andy Dalton threw three of his four touchdown passes in the first half, missing only one throw as the Bengals opened a 21-0 lead.
The Houston Texans were in devastating form in a 57-14 win over the Tennessee Titans, Deshaun Watson producing the best game in his young career by throwing four touchdowns.
The Los Angeles Rams are the highest-scoring team so far and they ended the Dallas Cowboys' eight-game home winning streak with a 35-30 road victory.
Elsewhere, the New York Jets edged out the Jacksonville Jaguars 23-20, the Detriot Lions beat the Minnesota Vikings 14-7 and the Pittsburgh Steelers were 26-9 winners against the Baltimore Ravens.
Jay Ajayi's London return did not go to plan as the British-born running back's Miami Dolphins were shut out in a 20-0 loss to the New Orleans Saints in the early game at Wembley.
The NFL's highest profile Englishman was playing in the city of his birth for the first time and had been the focus of attention in the build-up, with Twitter even making him the first player in the league to be assigned an emoji this week.
Yet there were plenty of emojis already available for the feelings he was displaying during an afternoon were he rushed for just 46 yards from 12 carries.
He could be seen displaying his frustration and anger throughout as a Miami side who went to the play-offs last year offered one of the meekest performances London has seen.