[6] McDermott, who signed an undisclosed deal on January 11, 2017, replaced Rex Ryan, who was fired along with his twin brother Rob on December 27, 2016.

With the defending Super Bowl champion New England Patriots losing 42–27 to the Kansas City Chiefs to kick off the 2017 NFL season and Hurricane Irma delaying the game between the Miami Dolphins and the Tampa Bay Buccaneers to Week 11, the Bills hoped to take advantage and grab first place in the AFC East by beating the Jets, who swept them in 2016.

Many former Panthers players and personnel made their return to Carolina as members of the Bills, including fullback Mike Tolbert, cornerback Leonard Johnson, wide receiver Kaelin Clay, general manager Brandon Beane and head coach Sean McDermott.

Unfortunately, despite the defense sacking Panthers quarterback Cam Newton six times and only allowing three field goals from Graham Gano, the Bills offense could not take advantage, only managing a 45-yard field goal from Steven Hauschka in the fourth quarter, the team's lowest points since losing 45–3 to the San Francisco 49ers in 2012.

Prior to the game, several members of both teams knelt during the national anthem in the wake of President Donald Trump's comments regarding NFL players who protested.

Already missing wideout Jordan Matthews, the Bills offense sputtered for the most part after tight end Charles Clay suffered a knee injury in the second quarter and was ruled out the rest of the game.

LeSean McCoy scored his first two touchdowns of the season as the Bills won a shootout match 30–27, with their final 10 points coming in the last three minutes of the game.

With Tampa Bay taking the lead after forcing McCoy to fumble and capitalizing with a Mike Evans touchdown pass from Jameis Winston, Tyrod Taylor led the Bills 75 yards downfield, connecting with newly signed receiver Deonte Thompson for 44 yards to help set up McCoy's second touchdown.

Tre'Davious White then forced the Buccaneers to fumble on their ensuing drive, setting up Steven Hauschka's game winning field goal.

[14] Note: Former Bills Garrison Sanborn and Ryan Fitzpatrick made their first return to New Era Field since signing with the Buccaneers in free agency.

This was the first week they were without All-Pro defensive lineman Marcell Dareus, who was traded to the Jacksonville Jaguars for a sixth-round draft pick just two days prior to the game.

LeSean McCoy led the team with over 180 yards from scrimmage and rookie linebacker Matt Milano also scored off a fumble recovery.

Though heavily favored to win, the Bills played poorly on defense and allowed the Jets to run for 194 yards and three rushing touchdowns.

The offense surrendered three fumbles which ultimately influenced the course of the game, despite receivers Zay Jones and Deonte Thompson catching their first touchdowns as members of the Bills.

After consecutive weeks of playing bad defense, the Bills were finally able to rebound, holding Kansas City to just 10 points as Tyrod Taylor returned to the starting lineup on offense.

Tre'Davious White sealed the win for Buffalo in the fourth quarter with an interception off Chiefs quarterback Alex Smith.

Perhaps the defining moment of the game occurred in the fourth quarter, when Tre'Davious White intercepted a pass intended for Rob Gronkowski.

The amount of snow on the ground did prove to be an advantage for the punters, since the ball did not bounce upon landing, making precision coffin corner punts easier.

[20] Nathan Peterman made his second start with Tyrod Taylor injured, and was able to post a respectable performance before leaving in the third quarter with a concussion.

Receiver Kelvin Benjamin caught a pass in the closing seconds of the second quarter that was initially ruled a touchdown by the on-field officials; however, the league's replay official, Alberto Riveron, determined that Benjamin did not have control of the ball until after his foot left the turf and Riveron overturned the touchdown, forcing the Bills to settle for a field goal.

At the end of the game, the Bills were still waiting for the final outcome between the Cincinnati Bengals and the Baltimore Ravens to determine their fates for the season.

With 49 seconds left in that game, Bengals quarterback Andy Dalton threw a 49-yard go-ahead touchdown pass to Tyler Boyd on a 4th-and-12 play to go up 31–27.