The Patriots stay at home for a matchup against the Tyrod Taylor-led Bills. On the first play of scrimmage, Brissett hit Edelman on a 90-yard catch-and-run to the Bills 1, but the play was nullified by a holding penalty on former Buffalo Bills player, Chris Hogan. The Patriots didn't get a first down and punted. Starting from their own 35, the Bills marched 65 yards in over 7 minutes, scoring on a 7-yard touchdown pass from Taylor to LeSean McCoy. After a Patriots three-and-out, the Bills marched to the Patriots 16, but settled for Dan Carpenter's 34-yard field goal on the second play of the second quarter, making the score 10-0. After forcing the Patriots to punt, the Bills drove 71 yards and Carpenter ended the drive with a 43-yard field goal, extending the lead to 13-0. The Patriots drove all the way to the Bills 18 on their ensuing possession, but Brissett was strip-sacked by Zach Brown with Preston Brown recovering for the Bills. Starting at their own 9, the Bills drove to their own 42, but punted. The Patriots punted as well, and the Bills led 13-0 at halftime.
After forcing the Bills to punt on the opening drive, the Patriots drove to the Bills 30, but Gostkowski missed a 48-yard field goal. The Bills countered, reaching the Patriots 29, but then Carpenter missed a 47-yard field goal. After yet another Patriots punt, Ben Tate returned the punt 18 yards to the Bills 30. The Bills reached the Patriots 26, and Carpenter nailed a 44-yard field goal stretching the score to 16-0. Midway through the fourth quarter, the Patriots drove all the way to the Bills 21, but turned the ball over on downs. After a Bills punt, the Patriots reached the Bills 44, but the clock ran out. With the loss the Patriots fell to 3–1.
This was the first shutout for the Patriots at home since 1993, as well as their first shutout loss since 2006. This was also the team's first shut out loss to the Bills since 2003.