In the wake of Buffalo's quarterback controversy, Doug Flutie was released by the Bills, prior to the season and followed Butler to San Diego. Buffalo named Rob Johnson their starting quarterback for the 2001 season, which would ultimately be his last in Buffalo. Bills defensive endMarcellus Wiley and linebackerJohn Holecek also left Buffalo for San Diego in 2001, leaving a gap in Buffalo's defense. The special teams also saw a major overhaul. Placekicker Steve Christie was also among the defectors to San Diego, forcing the Bills to sign rookie Jake Arians (son of longtime offensive coordinator Bruce Arians) as a replacement, then after several weeks of Arians's poor play, Shayne Graham. Chris Mohr left for the Atlanta Falcons and was replaced by Brian Moorman, who would stay with the team for the next eleven seasons.
Buffalo's 2001 draft was general manager Tom Donahoe first with the team. The Bills' first three draft picks — Nate Clements, Aaron Schobel and Travis Henry — went on to make the Pro Bowl with the Bills.