Miller has missed one game since he left the Bills' November 24 win over the Detroit Lions but exploratory surgery on Tuesday revealed the ACL injury. Miller had previously said he sustained damage to his meniscus.
"Very unfortunate situation for Von obviously and our team," Bills head coach Sean McDermott told reporters.
"We care for him obviously, like we would any player. We know how much this means to him in terms of playing and being with the team.
"So we look forward to getting him back, obviously off the field for the rest of the season and his leadership. And we're certainly thinking about him as he recovers here."
A week after suffering the injury the Bills placed Miller on injured reserve, which meant he would miss at least the next four games, and the hope was that he would be able to return at some point during the season.
Miller signed with Buffalo in March a month after winning a Super Bowl with the Los Angeles Rams.
He also won a Super Bowl with the Denver Broncos in 2016 and was named the most valuable player of the NFL's championship game that year.
Miller's arrival in Buffalo provided a significant upgrade to the Bills' pass rush and through 11 games the linebacker recorded a team-high eight sacks along with 21 tackles, two passes defended and a forced fumble.
The Bills, who began the season as favourites to win the Super Bowl, have five games left in the regular season and lead the AFC East division with a 9-3 record going into Sunday's game against the New York Jets.
According to a report on the Bills website, the team expect Miller to be an important leadership voice in the locker room for the stretch run and are optimistic he will return to play sometime in the 2023 season.
