Previous head coach Wade Phillips was fired, and was replaced by Tennessee Titans defensive coordinator Gregg Williams.
At 3–13, they finished the season with the worst record in the whole American Football Conference and at last place in the AFC East division for the first time since 1985.
In the wake of Buffalo's 1999-2000 quarterback controversy, Doug Flutie was released by the Bills prior to the season and followed Butler to San Diego.
Running backs (RB) Wide receivers (WR) Tight ends (TE) Defensive linemen (DL) Defensive backs (DB) Special teams Reserve at Ralph Wilson Stadium, Orchard Park, New York The Gregg Williams era began inauspiciously in this game against former Bills linebacker Jim Haslett and the New Orleans Saints.
Surprisingly, the Bills struck first with rookie cornerback Nate Clements intercepting a Peyton Manning pass and returning it 48 yards for a touchdown.
In the third quarter Colts linebacker Rob Morris was ejected for unnecessary roughness and for inadvertently bumping up into referee Bill Carolo's mouth.
Near the end of the first quarter, Travis Henry fumbled in Steeler territory, and Dewayne Washington returned the loose ball 63 yards for a touchdown to open the scoring, 7–0.
[3] at Ralph Wilson Stadium, Orchard Park, New York In danger of falling to their worst start in over a decade, the Bills opened this matchup by going into their bag of tricks.
Rookie punter Brian Moorman attempted a surprise onside kick on the opening play of the game, and the Bills recovered.
Alex Van Pelt played well in his relief appearance, and after Curtis Martin added another touchdown to make the score 28–9 Jets, the Bills began to mount a comeback.
Arians made a 46-yard field goal with 1:03 to go to give the Bills the lead, then safety Travares Tillman intercepted a Brunell pass on the next drive with 44 seconds left to seal the win.
In the fourth quarter, Jason Perry intercepted a Rob Johnson pass and returned it 37 yards for a touchdown to make the score 20–10 Chargers.
[8] at Foxboro Stadium, Foxborough, Massachusetts Tom Brady's reign of terror against the Bills began with this Week 9 matchup that saw the Patriots improve to over .500 for the first time in their first Super Bowl season.
However, on the ensuing possession, defensive end Kendrick Office sacked Brady and forced him to fumble, with fellow lineman Jay Foreman recovering the ball to put the Bills back in the game.
The game was Rob Johnson's final appearance as a Buffalo Bill, as Alex Van Pelt started for the remainder of the season.
[9] at Ralph Wilson Stadium, Orchard Park, New York The Bills kicked off a two-week homestand with a home matchup against the Seahawks.
In the second quarter, Matt Hasselbeck found rookie wide receiver Koren Robinson for a 7-yard touchdown to make the score 10–0 Seattle.
During halftime, longtime quarterback Jim Kelly's name was added to the Bills Wall of Fame, and his number 12 jersey was retired.
On the opening drive of the second half, Van Pelt threw a 54-yard touchdown pass to Moulds, and the score was 21–10 Bills heading into the final quarter.
On the opening play of the quarter, Jay Fiedler found tight end Jed Weaver for an 8-yard touchdown pass to narrow the score 21–17.
On the very next play, Nate Clements fumbled the kick return, and Dolphins corner Patrick Surtain recovered at the Bills' 42 yard line.
Alex Van Pelt attempted to get the Bills down the field for a game-tying touchdown in the game's final moments, but while spiking the ball at the Dolphins' 32-yard line to set up one more opportunity, the clock ran out.
After a field goal by the Bills' new kicker Shayne Graham (who replaced Jake Arians starting in the 49ers game), Weinke found tight end Kris Mangum for a 2-yard touchdown to make the score 24–6 Panthers with 36 seconds to go in the half.
[14] at Ralph Wilson Stadium, Orchard Park, New York The Bills' final home game of the year was a defensive slugfest against the Patriots that did not feature a single touchdown.
Perhaps representative of the defensive battle, the game's most memorable play came in the third quarter when Nate Clements blasted Tom Brady on a QB scramble after he found no receivers open, sending his helmet flying in the process.
Tom Brady completed a pass to wide receiver David Patten, who fumbled upon being tackled by safety Keion Carpenter along the sideline.
On the next play, former Bill Antowain Smith broke free for a 38-yard run to put the Patriots in the red zone, setting up Adam Vinatieri for a game-winning 23-yard field goal.
In the third quarter, the Bills fell behind 16–14 after a Jay Feely field goal, but regained the lead with Shawn Bryson outrunning the Falcons for a 68-yard touchdown to make the score 20–16.
Alex Van Pelt drove the Bills 82 yards down the field, then threw a 3-yard touchdown pass to Eric Moulds with just 48 seconds remaining to tie the score at 30–30.
[16] at Giants Stadium, East Rutherford, New Jersey Despite the struggles the Bills faced all season, they were able to play spoiler in a late-season game against the New York Jets, who were fighting for a playoff spot in the crowded AFC race.