The 2019 season was the Buffalo Bills' 60th overall, 50th in the National Football League (NFL), fifth full under the ownership of Terry and Kim Pegula and third under the head coach/general manager tandem of Sean McDermott and Brandon Beane.

The Bills freed up cap space after paying off the dead money for players from the Doug Whaley era they had either cut or traded over the past two offseasons, including WR Sammy Watkins, CB Ronald Darby and DT Marcell Dareus.

To address the team's offensive woes from the previous season, numerous offensive players such as WRs John Brown, Cole Beasley and Andre Roberts, C Mitch Morse, RBs Frank Gore and T. J. Yeldon and others were added in free agency, with Beane angrily dismissing the notion that "free agents don't want to play for Buffalo.

Bengals QB Andy Dalton was intercepted by CB Tre'Davious White for the second time on Cincinnati's ensuing drive, sealing a 21–17 victory for Buffalo.

After leading the Bills to 10 points, Allen was knocked out of the game in the fourth quarter after sustaining a helmet-to-helmet hit with Patriots CB Jonathan Jones during a scramble.

The Patriots defense stifled backup quarterback Matt Barkley, keeping the Bills offense out of the end zone for the rest of the game.

In another defensive game, Buffalo scored first with an Allen pass to TE Lee Smith in the second quarter, while Titans QB Marcus Mariota was sacked four times in the first half.

Following the miss, the Bills drove 80 yards down the field, capitalizing with a go-ahead touchdown from Allen to receiver Duke Williams as Tennessee was unable to respond.

Against the winless Dolphins, the Bills trailed at halftime 14–9 following a strong second quarter from Miami QB Ryan Fitzpatrick, who was Buffalo's starter from 2009-2012.

The Bills then regained the lead with two Allen touchdown passes to WRs John Brown and Cole Beasley, respectively, with the latter occurring after White forced the Dolphins to fumble near their 30-yard line.

Though the Dolphins scored again later in the fourth quarter, the Bills iced the game after safety Micah Hyde returned Miami's ensuing onside kick for a 45-yard touchdown.

The Bills drove to the Cleveland 35-yard line on the ensuing drive, but K Stephen Hauschka missed the potential game-tying field goal attempt, sealing the loss for Buffalo and dropping them to 6–3 on the season.

Defensively, the Bills had another strong performance and shut down the Denver offense, limiting the Broncos to just 134 net yards and a 45-yard field goal midway through the third quarter in addition to sacking QB Brandon Allen four times.

The Bills would respond in the second quarter when Beasley, making his first return to Dallas since signing with Buffalo in free agency, caught a 25-yard touchdown pass from Allen.

Baltimore took a commanding 17–6 lead three plays into the third quarter after Jackson found TE Hayden Hurst for a 61-yard touchdown through blown coverage and extended their lead with a long touchdown drive following a Bills field goal and a missed pass interference call after Ravens CB Jimmy Smith pushed Bills WR Robert Foster in the back.

Despite New England holding the ball for much of the first half, Buffalo tied it up at halftime after stopping a fourth-down conversion, then subsequently marching down the field in 38 seconds and capitalizing with a Josh Allen touchdown pass to offensive tackle Dion Dawkins.

Similar to the game against the Ravens, Buffalo then drove down the field into the redzone on its final possession, but was unable to score the game-tying touchdown as the drive stalled at the New England 14-yard line.

[41] Later in the weekend, the other AFC teams contending for Wild Card spots in the playoffs, namely the Pittsburgh Steelers and the Tennessee Titans, both lost to fall to 8–7.

In their third consecutive playoff game against the AFC South, the Bills jumped out to an early lead including a trick play touchdown from receiver John Brown to Josh Allen on their first drive, and were able to contain Texans quarterback Deshaun Watson in the first half.

After exchanging turnovers on downs, the Bills were able to get the ball back with just over a minute remaining and set up a field goal to force the game into overtime.