In week 3 of the season, the Bills broke a 15-game losing streak that the team had accrued against the New England Patriots that dated to opening day of the 2003 season; Buffalo defeated the Patriots, 34–31. In doing so, the 2011 Bills became the only team since before 1950 (when comprehensive statistical record keeping began) to win two consecutive games in which they trailed by 18 or more points; they overcame a 21–3 deficit to Oakland in Week Two, and a 21–0 deficit to New England in Week Three.
Incidentally, Buffalo's loss to the Cincinnati Bengals the following week was the Bills' first loss to Cincinnati since the 1988 AFC Championship game; that streak had been the longest winning streak by one team over another after Buffalo snapped their losing streak to New England.
The Bills started the season with a 5–2 record, positioned to make the playoffs, before losing eight of their final nine games, eliminating them from the playoffs.
Wide receiver Stevie Johnson set a franchise mark as the only receiver in Bills history to record two consecutive 1,000-yard seasons. No other Bills receiver—including Andre Reed, James Lofton, Eric Moulds or Lee Evans—had done so with Buffalo. Buffalo's offense only surrendered 23 sacks all season, the fewest in the NFL.
The Bills also lost two wide receivers that did not contribute significantly during the 2011 season, Marcus Easley and Roscoe Parrish, to IR (the former missing his second full season, the latter coming off a strong 2010 season), and two kickers, incumbent starter Rian Lindell and replacement Dave Rayner; the Bills were compelled to sign a third-string kicker, Brandon Coutu, for the final game of the 2011 season against New England. Rookie Marcell Dareus also admitted to playing much of the season with numerous injuries, but continued to stay on the field out of a personal obligation to the team. Starting quarterback Ryan Fitzpatrick also sustained an undisclosed injury in the middle of the season, but was never listed on the injury report (nor was the injury ever specified), and Fitzpatrick continued to play the rest of the season.
In the first seven games of the season (of which the Bills won five), the Bills had a +9 turnover differential (18 takeaways, 9 giveaways); from Week Nine until the end of the season, the Bills gave the ball away 21 times, with only 12 takeaways. Quarterback Ryan Fitzpatrick started the season strongly, posting a 97.8 passer rating and a 14/7 touchdown-interception ratio through the first seven games; in the final nine games, Fitzpatrick threw ten touchdowns, and 16 interceptions, with a 66.5 quarterback rating in that span. His 23 total interceptions were the most thrown by any quarterback in the league in 2011. He threw only 5 interceptions total in the Bills' six wins, and 18 in their ten losses. Bills wide receiver David Nelson stated that Fitzpatrick was injured by Redskins linebacker London Fletcher in Week Eight, the last win before the losing streak began. Said Nelson, "A lot of people don't know, but Fitz during the Washington game actually cracked a couple of ribs. So after that, he was playing hurt."
On February 9, 2011, the Bills announced that the team planned to introduce redesigned uniforms for the 2011 season. No details were given on what the uniforms would look like, but it was said that the charging buffalo logo would be kept. Later reports leaked by a Madden NFL 12 trailer, and said to be confirmed by the league, indicated the team would be adopting the uniforms the team wore between 1975 and 1983. It was also announced that an official unveiling of the new uniforms would be at a fan appreciation event later in the summer. The uniforms were unveiled on June 24, 2011. The team also announced that the U.S. military will be involved in the unveiling.
Trying to snap a two-game losing streak, the Bills flew to Sun Life Stadium for a Week 11 AFC East showdown with the Miami Dolphins. Buffalo delivered the game's opening punch in the first quarter with a 30-yard field goal from kicker Dave Rayner, but the Dolphins answered with quarterback Matt Moore completing a 1-yard touchdown pass to tight end Anthony Fasano, followed by running back Reggie Bush getting a 5-yard touchdown run. Miami added onto their lead in the second quarter with Moore completing a 12-yard touchdown pass to fullback Charles Clay and a 4-yard touchdown pass to wide receiver Davone Bess. The Bills would close out the half with a 56-yard field goal from Rayner.
The Dolphins added onto Buffalo's misery in the third quarter with running back Lex Hilliard recovering a blocked punt in the endzone for a touchdown. The Bills tried to rally in the fourth quarter as rookie linebacker Kelvin Sheppard tackled running back Daniel Thomas in the endzone for a safety, but Miami's lead proved to be too much to overcome.
Buffalo's final game of the season was a 49–21 loss to New England on New Year's Day 2012. In a mirror image of Week Three, the Bills opened a 21–0 on New England, before giving up 49 unanswered points to the high-powered Patriot offense. Head coach Chan Gailey benched wide receiver Stevie Johnson after Johnson caught a touchdown, then lifted his jersey to reveal "Happy New Year" on his shirt. The touchdown was Johnson's final play of the season as he was benched for the rest of the game. According to Pro-Football-Reference.com, New England, who won by 28, became the first team in NFL history to win a game by more than eight points after trailing by more than 20 points after one quarter. It was also the first time in a two-game season series that the winning team in each game overcame a deficit of more than 17 points. With the loss, the Bills finished with a 6–10 record and secured the 10th pick in the 2012 NFL Draft.
^Fred Jackson's deactivation was somewhat controversial, as it disqualified him from Pro Bowl consideration; Jackson, whose leg was expected to heal by the time of the Pro Bowl, was a contender for the game, and would have been the only Bill to make the team, since the Bills had no players named to the contest. At the end of Week Ten (the game in which Jackson was injured), he was leading the NFL in rushing yards, with 917.
^After the unveiling, there was a movie screening The Blind Side which was scheduled to round out the unveiling and fan appreciation event. Fans could vote for which film they want to see on the Bills' Facebook page.