Josh Allen marked his side's home opener with four scoring tosses including three to wide receiver Stefon Diggs as the Bills backed up from their 31-10 victory over the Super Bowl champion Los Angeles Rams.
Allen topped 300 yards passing for the 15th time of his career, completing 26 of 38 attempts for 317 yards, before sitting out the entire fourth quarter. Diggs, meanwhile had 12 catches for 148 yards, achieving the rare feat of exceeding 100 yards in each of his first two games.
The Bills' secondary limited the visitors to 182 yards on offence and 12 first downs, while having two sacks and four turnovers themselves.
Allen did not care that the victory was achieved against a side which had beaten Buffalo in each of the past two campaigns.
He said after the game: "It doesn't matter who it's against. Like, that's a good team that we played. For us to go do that was great."
The Philadelphia Eagles, meanwhile, defeated the Minnesota Vikings after Jalen Hurts bounced back from a horror outing against the Detroit Lions in which he only completed 18 of his 32 attempted passes.
Accuracy was not an issue for the second-year quarterback on Monday as he hit five receivers on five-for-five passing, going on to record 301 yards through the air in the first half as his side went to the break up 24-7.
Hurts finished with 333 yards and a touchdown courtesy of his arm, while he also collected two rushing touchdown as the score remained the same throughout the second half and the home team improved to 2-0 on the season.
Minnesota quarterback Kirk Cousins had a forgettable night on the road, scoring once but also being picked off three times as he completed 27 of 46 passes.