On May 9, 2017, Beane was hired by Buffalo as the general manager, joining former Panthers defensive coordinator Sean McDermott, who had been hired as head coach. After the Bills fired previous general manager Doug Whaley, they opted to hire someone familiar to McDermott due to conflicts within the previous head coach-GM tandems under Whaley.

Within the first season, Beane traded away many of the players Whaley had signed, drafted, or extended, including receiver Sammy Watkins, cornerback Ronald Darby, linebacker Reggie Ragland, and defensive tackle Marcell Dareus. Though Beane arguably had his sights on a long-term rebuild while purging unfavorable contracts for the Bills, some sports commentators criticized his tactics. In 2017, Beane's first season with the team, the Bills ended their 17-year playoff drought. Beane has since drafted players such as quarterback Josh Allen, linebacker Tremaine Edmunds, and defensive tackle Ed Oliver and brought in numerous offensive free agents with the team's new cap space. On December 10, 2020, Beane signed a contract extension through 2025.