The 2018 season was the Buffalo Bills' 59th overall, 49th in the National Football League (NFL), fourth full under the ownership of Terry and Kim Pegula and second under the head coach/general manager tandem of Sean McDermott and Brandon Beane.

They were officially eliminated from playoff contention the following week with a 27–23 loss to the New York Jets, ultimately finishing with a 6–10 record as numerous players from the previous season departed via trades, roster cuts or retirement.

On May 1, 2018, three weeks after the 2017–18 Buffalo Sabres season ended, team president Russ Brandon announced his resignation from Pegula Sports and Entertainment.

Played in heavy rain, the lopsided game saw a dominant performance from Ravens QB Joe Flacco, who completed 25 of 34 passes for 236 yards and three touchdowns against the Bills defense before handing the reigns off to rookie Lamar Jackson.

Bills QB Nathan Peterman completed just 5/18 attempts for 24 yards and two interceptions, good for a 0.0 passer rating before being benched for rookie Josh Allen in the third quarter.

However, after Houston tied the game at 13–13 late in the fourth quarter, Peterman threw two interceptions, including a pick-six to Texans CB Johnathan Joseph, which sealed the loss for Buffalo, dropping the team to 2–4.

After Allen's injury in the previous game against the Texans and Peterman's poor performance in his relief, recently signed third-stringer Derek Anderson was named the starter on October 17, 2018.

Sadly, not even Anderson could help the Bills, who suffered their worst loss since Week 1, as they were on the wrong end of a final score of 37–5, dropping to 2–5.

In the first Monday Night Football game hosted by Buffalo since losing to the Cleveland Browns, the Bills defense held up again, holding QB Tom Brady out of the end zone and limiting the Patriots to three Stephen Gostkowski field goals in the first half, but a late rushing touchdown by Patriots RB James White and a subsequent pick-six by CB Devin McCourty sealed yet another Patriots win over the Bills, with McCourty's interception occurring immediately after an overturned touchdown pass from Derek Anderson to Bills TE Jason Croom.

After Derek Anderson suffered a concussion in the previous game, Nathan Peterman made the start with the team with Josh Allen still out.

[37] Barkley's efficient performance in the win, coupled with the improving health of Josh Allen, led to the release of Nathan Peterman the following evening.

Buffalo outgained Miami in terms of total offense, with 415 yards compared to just 175, but their struggles on special teams and penalties gave the Dolphins short fields and allowed QB Ryan Tannehill to pass for three touchdowns, including the eventual 13-yard game winner to WR Kenny Stills.

The game came down to the final moments, when Josh Allen, who compiled 366 total yards on the day, attempted a fourth down pass to TE Charles Clay, who dropped it just outside the end zone.

With running backs LeSean McCoy and Chris Ivory both injured, the Bills relied offensively on Josh Allen and backup halfbacks Marcus Murphy and Keith Ford, who both left the game at some point with their own injuries.

Lions kicker Matt Prater missed a field goal and was unable to kick an extra point earlier due to a botched snap, allowing the Bills to win 14–13.

This was also the final NFL game for longtime defensive tackle Kyle Williams, as he announced his intention to retire after the season's conclusion.