Beane spent the past 19 years with the Panthers. The past two seasons, he was the Panthers' assistant general manager, and he spent seven years as the team's director of football operations.
He agreed to a five-year contract with the Bills, according to multiple reports.
Bills owner and CEO Terry Pegula met with Beane for a second interview on Tuesday and released a statement following the hiring.
"During our search for a new general manager, Brandon stood out to (my wife) Kim and I as he embodies the type of leader and type of person we want in our organization," Pegula said in his statement. "Brandon has excelled in a variety of roles for a Panthers team that has consistently competed at a high level in this league. We feel his vast understanding and experience in many facets of football operations will be invaluable to our club moving forward. We also believe his vision for the Buffalo Bills combined with his detailed approach will help build a foundation for sustained success. We are pleased to welcome Brandon and his family to Buffalo."
The Bills offer a significant challenge. They were 7-9 in 2016 and have had only one winning season since 2004.
The Bills have not qualified for the playoffs since 1999, which is the longest postseason drought by any team in a major professional sport.
Buffalo fired general manager Doug Whaley one day after the conclusion of the NFL Draft.
As the Panthers assistant GM and director of football operations, Beane gained experience in nearly every facet of the Panthers personnel department. He worked under Dave Gettleman, who has been the Panthers' general manager since 2013.
In 2012, Beane was named the Panthers' interim general manager and held that role for the final 10 games of the season.