The 2021 season was the Buffalo Bills' 52nd in the National Football League (NFL), seventh full under the ownership of Terry and Kim Pegula, and their fifth under the head coach/general manager tandem of Sean McDermott and Brandon Beane.

They finished the regular season at 11–6 to obtain the #3 seed for the playoffs, also marking their third consecutive postseason berth and fourth in five years.

The Bills defeated their AFC East rival New England Patriots in the wild card round, a game marked by them becoming the first NFL team to score a touchdown on every offensive drive.

Despite a 10–0 halftime lead and a strong performance from the Buffalo defense, the Bills' hopes for a third straight Week 1 victory were dashed after Pittsburgh scored 20 unanswered points in the second half, including a blocked punt returned for a touchdown.

Buffalo rebounded from its loss the prior week with the most dominant win over division rival Miami in franchise history.

Despite an early interception, Allen completed two touchdown passes to tight end Dawson Knox and led the Bills to 33 points before backup Mitchell Trubisky was substituted on in the fourth quarter.

[8] In the final moments of a back-and-forth shootout on Monday Night Football, in which the lead changed seven times, the Titans defensive line stopped Josh Allen on a fourth-down quarterback sneak at the Tennessee 3-yard line, and Buffalo narrowly lost 34–31, falling to 4–2 ahead of its bye week.

The Dolphins, who entered the game at 1–6, dominated the time of possession in the first half and limited Buffalo's offense to a field goal; however, they also squandered two scoring opportunities in the red zone, culminating in a 3–3 tie at halftime.

The Bills would score two unanswered touchdowns to Gabe Davis and Stefon Diggs after halftime en route to a 26–11 win, their seventh straight over Miami.

After allowing field goals on each of their first two drives, the Jaguars defense had their way with the Bills offensive line, which was missing Jon Feliciano and Spencer Brown due to injury.

[12] Jacksonville pulled off one of the biggest upsets in NFL history, defeating the Bills 9–6 and winning their first game in North America since Week 1 of the 2020 season.

The Bills defense, missing key run-stoppers Star Lotulelei and Tremaine Edmunds, struggled to contain Colts RB Jonathan Taylor, who scored five total touchdowns from scrimmage.

[16] To make matters worse, the Buffalo offense and special teams unit committed key turnovers, contributing to a 41–15 blowout loss.

Josh Allen continued to struggle with interceptions, throwing two in the second quarter, but also threw four touchdown passes, including two to Dawson Knox, as Buffalo routed New Orleans 31–6 to improve to 7–4.

The Buccaneers raced to a 24–3 halftime lead under former Patriots quarterback Tom Brady, along with a strong first-half performance by running back Leonard Fournette and a furious pass rush that largely shut down Josh Allen and the Bills' offense, which did not hand off the ball to a running back in the first half, the first time an NFL team had not done so since 1991.

Buffalo avenged its Monday Night loss to the Patriots earlier in December, as Josh Allen passed for over 300 yards and 3 touchdowns and was not sacked during the game.

New England relied heavily on its run game again, with Damien Harris scoring 3 touchdowns, but was forced to pass more with rookie quarterback Mac Jones, who completed less than 50 percent of his throws and was intercepted twice by Micah Hyde.

Despite Allen turning in one of the worst passing performances of his career, he and running back Devin Singletary combined for four rushing touchdowns as Buffalo overcame 3 turnovers and a Falcons lead at halftime to win 29–15, clinching a playoff berth for the fourth time in five years.

[28] A New England loss, combined with a subsequent victory by the Las Vegas Raiders late that night, sealed the 3rd seed for the Bills, and the Patriots as their opponent for the Wild Card game.

Additionally, they became the only team in NFL history to not attempt a field goal, punt, or commit a turnover in a single game (regular season or postseason).

Buffalo took a 36–33 lead with 13 seconds left, but controversially opted to eschew a squib kick for a traditional kickoff out of the endzone for a touchback setting up the Chiefs at their own 25-yard-line with all three of their timeouts remaining.