The Bills began their season at Gillette Stadium for an AFL Legacy duel with their AFC East rival, the New England Patriots, in the first game of a MNF doubleheader.

Buffalo got off to a fast start in the first quarter as quarterback Trent Edwards completed an 11-yard touchdown pass to rookie tight end Shawn Nelson.

With just over 5 minutes to play, The Patriots would strike back as quarterback Tom Brady completed an 18-yard touchdown pass to tight end Benjamin Watson (with a failed two-point conversion).

Hoping to rebound from a tough loss to the Patriots, the Bills would play their Week 2 home opener in an interconference duel with the Tampa Bay Buccaneers.

The Buccaneers would get on the board in the second quarter as quarterback Byron Leftwich completed a 42-yard touchdown pass to tight end Kellen Winslow, while Buffalo replied with Lindell getting a 43-yard field goal.

Tampa Bay would close out the half as Leftwich completed an 8-yard touchdown pass to running back Carnell "Cadillac" Williams.

After a scoreless third quarter, the Bills began to pull away as Lindell got a 43-yard field goal and Edwards completed a 43-yard touchdown pass to wide receiver Terrell Owens.

The Buccaneers tried to rally as Leftwich completed a 6-yard touchdown pass to tight end Jerramy Stevens (with a failed two-point conversion), yet Buffalo closed out the game with Lindell nailing a 20-yard field goal.

Coming off their win the Buccaneers, the Bills stayed at home for a Week 3 interconference duel with the New Orleans Saints.

The Bills would answer in the second quarter on a fake field goal attempt, punter Brian Moorman threw a 25-yard touchdown pass to defensive end Ryan Denney.

Hoping to rebound from their home loss to the Saints, the Bills flew to Land Shark Stadium for a Week 4 AFC East duel with the Miami Dolphins.

After a scoreless first quarter, Buffalo would find themselves trailing in the second as Dolphins kicker Dan Carpenter got a 33-yard field goal, followed by cornerback Vontae Davis returning an interception 23 yards for a touchdown.

The Bills, hoping to shake off a loss to the winless Miami Dolphins on the road the week before, faced the 0–4 Cleveland Browns at Ralph Wilson Stadium.

[3] Trying to snap a three-game losing streak, the Bills flew to The Meadowlands for a Week 6 AFC East duel with the New York Jets.

In the third quarter, the Bills fought back as Lindell nailed a 25-yard field goal, followed by quarterback Ryan Fitzpatrick completing a 37-yard touchdown pass to wide receiver Lee Evans.

Both teams would fight hard throughout the fourth quarter and eventually, Lindell got a chance to kick a last-second field goal.

Coming off their thrilling overtime road win over the Jets, the Bills flew to Bank of America Stadium for a Week 7 interconference duel with the Carolina Panthers.

In the first quarter, Buffalo struck first with a trick play as running back Fred Jackson completed a 27-yard touchdown pass to wide receiver Lee Evans.

In the third quarter Buffalo took the lead with QB Ryan Fitzpatrick making a 98-yard touchdown pass to WR Terrell Owens (with a failed 2-point conversion attempt).

Trying to snap a three-game losing streak, the Bills went home, donned their throwback uniforms (again), and played a Week 12 AFC East rematch with the Miami Dolphins.

In their second-ever regular season game north of the border, Buffalo traveled to Toronto to take on divisional rivals the New York Jets.

The teams went scoreless in the third quarter that was notable for Sanchez suffering a sprained Posterior cruciate ligament to his right knee.

Buffalo had a chance to take the lead or at least tie in the final two minutes, but quarterback Ryan Fitzpatrick threw an interception to Darrelle Revis, sealing the victory for the Jets.