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.
The Bills started the season with a promising 5-2 record. However, the Bills' season was plagued by injuries to key starters, including linebacker Shawne Merriman, center Eric Wood, cornerback Terrence McGee, star nose tackleKyle Williams, and star running back Fred Jackson, all of whom were placed on injured reserve to end their respective seasons (Jackson's was somewhat controversial, as it disqualified him from Pro Bowl consideration; Jackson, whose leg is expected to heal by the time of the Pro Bowl was a contender for the game). The Bills also lost two wide receivers, Marcus Easley and Roscoe Parrish, to IR.  The Bills, after starting the season 5-2, have lost all five of the subsequent games to the New York Jets (twice), Dallas Cowboys, Miami Dolphins, and Tennessee Titans.
On February 9, 2011, the Bills announced that the team planned to introduce redesigned uniforms for the 2011 NFL 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 date of the new uniform unveiling was June 24, 2011. The team also announced that the U.S. military will be involved in the unveiling. 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.
The Bills wore their white jerseys at home against the New York Jets in Week Nine, which the team hadn't done since 1986 vs. Indianapolis.  The "White Out" did not prove successful, however, as the Bills lost to the Jets 27-11.
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.