After acquiring players such as Stefon Diggs, Mario Addison, and A. J. Klein during the offseason, the Bills offense, led by quarterback Josh Allen, took another step forward, scoring an at the time franchise-record 501 points and leading the Bills to 13 wins in the regular season, and their first playoff wins and first AFC Championship appearance of the 21st century.

In addition to returning to the playoffs for the third time in four years after previously going 17 consecutive seasons without a playoff appearance, the team won the AFC East division title for the first time since 1995 (during the Marv Levy/Jim Kelly era) after a 48–19 win over the Denver Broncos in Week 15, becoming only the second team other than the 2008 Miami Dolphins to win the division over the New England Patriots since the New York Jets in 2002.

The defense largely shut down the Jets' offense aside from a field goal, a 69-yard touchdown pass from Sam Darnold to Jamison Crowder and a garbage-time touchdown in the fourth quarter, though rookie kicker Tyler Bass struggled in his debut, missing two of his four field goal attempts.

In a back-and-forth affair against the rival Dolphins and former Bills quarterback Ryan Fitzpatrick, Josh Allen sealed the game for the Bills with two fourth-quarter touchdown passes to rookie Gabe Davis and John Brown, respectively, as the defense was playing without starting linebackers Tremaine Edmunds and Matt Milano.

Stefon Diggs also caught his first touchdown as a Buffalo Bill, which occurred during a power outage at Hard Rock Stadium in the second quarter that temporarily prevented CBS from airing the game.

Buffalo raced to a 28–3 lead in the middle of the third quarter, but after a pass from Josh Allen to TE Tyler Kroft was controversially ruled an interception for Los Angeles as Rams DB John Johnson III grabbed the ball moments after Kroft caught it, the Rams stormed back with five scoring drives to erase the deficit and take the lead in the fourth quarter.

Late in the second quarter, Allen scrambled and found Stefon Diggs for a 9-yard gain, but took a big hit from Raiders DE Arden Key, resulting in an injury to his left shoulder.

To make matters worse, three turnovers by Buffalo allowed for short fields and quick touchdowns for the Titans.

Despite holding the high-powered Kansas City offense to 13 points in the first half of a rain-soaked game postponed from the previous Thursday (due to the Titans game being pushed back to the previous Tuesday), the Bills defense was not able to contain Chiefs rookie RB Clyde Edwards-Helaire, who led Kansas City to 245 rushing yards, while the Bills offense was bottled up for the most part, despite numerous pass-interference penalties called on the Chiefs secondary and two Josh Allen TD passes to Diggs and Beasley.

Despite early struggles, Buffalo's defense was outstanding after halftime, allowing just 4 total yards to the Jets offense in the second half.

In the Bills' return to the site of the Hail Murray play three weeks earlier, Josh Allen and Cole Beasley led the offense in an effective showing, while the defense kept a stout 49ers rushing offense in check for the most part with linebacker Matt Milano returning from injured reserve.

"[26] The Sunday Night Football matchup was a repeat from Week 15 of the 2019 season, when the Bills traveled to Pittsburgh and won 17–10 to clinch a playoff berth.

The Bills then scored on a field goal drive and a 51-yard pick six of Roethlisberger by Taron Johnson to go up 9–7 at halftime, a lead they would never relinquish.

Josh Allen joined Drew Bledsoe in 2002 as the only quarterbacks in franchise history to surpass 4,000 passing yards in a season.

After a close first quarter, in which the Bills were leading 10–9 following a 9-yard Cam Newton touchdown run, the Bills offense scored 28 unanswered points en route to a 38–9 blowout victory on the final Monday Night Football game of the season, sweeping the Patriots for the first time since 1999 and clinching their first 12-win season since 1993.

In a rematch from Week 2, the Bills closed out the regular season hosting the Dolphins, who needed a win to make the playoffs.

The Dolphins were forced to start rookie QB Tua Tagovailoa, as Ryan Fitzpatrick tested positive for COVID-19.

Unfortunately for the Dolphins, Tagovailoa had his worst performance of the season, as he had three interceptions (one of which was returned for a TD by Bills CB Josh Norman), despite passing for a career-high 361 yards.

Despite Allen being replaced in the second half by Matt Barkley, the Bills continued their dominating performance of the previous five weeks.

Despite only playing for one half, Josh Allen still broke the single season record for most passing yards by a QB in franchise history.

In a windy game which saw three missed field goals in the first half alone (two by the league's best kicker in Justin Tucker and one by Bills rookie Tyler Bass), the Bills scored the first touchdown of the game in the third quarter on a three-yard pass from Josh Allen to Stefon Diggs to take a 10–3 lead.

In the fourth quarter, Allen's pass intended for receiver John Brown was tipped and intercepted, leading to the Chiefs' final touchdown of the night.

The Bills followed up with a scoring drive on a Josh Allen touchdown pass to Isaiah McKenzie, followed by an unsuccessful two-point attempt, and a successful onside kick recovery leading to a field goal.