Miller tore the ACL in his right knee midway through the first quarter of Sunday's 37-13 victory over the Houston Texans. Miller underwent an MRI on Monday morning, and the exam confirmed what some team officials had feared after the game.
"It's definitely going to be a blow," Broncos executive vice president of football operations John Elway said on his weekly podcast, according to the team's website. "But I think that we've done a good job of handling adversity throughout the year.
"This is another bump in the road for us. Obviously Von is a big part of that defense, but I think that we were able to win six games when he wasn't available, so we'll have to pick it up for him. I feel bad for Von, because Von has done a lot of work to get back to where he is and was starting to hit his stride late in the year."
The two-time Pro Bowl selection is expected to undergo surgery in two to three weeks and face a recovery period of six to nine months, which would keep him out of the team's offseason program and likely at least some of training camp. Miller played in only nine games this season. He was suspended the first six games for violating the league's substance abuse policy.
Miller may seek a second opinion over the next couple of weeks.
Coach John Fox said after Sunday's game that Miller's fate was "in the medical people's hands right now."
Miller left the game after his leg buckled as he was fighting to get off a block on a 3-yard completion from Matt Schaub to Keshawn Martin. Both Miller and defensive end Shaun Phillips were down after the play, but Phillips got up and walked off the field as Miller was helped to the sideline.
According to teammates, Miller was not using crutches after the game and told others he did not have significant pain in the knee. After a preliminary exam by team doctors in the locker room, however, several people with the Broncos said they believed Miller damaged his ACL.
Miller had one tackle Sunday and finishes with 33. He's tied for second on the team with five sacks.
Miller has 35 career sacks, fifth-most in the NFL since his rookie season of 2011, according to ESPN Stats & Information.
Nate Irving played in Miller's strongside linebacker spot in the Broncos' base defense the rest of the way Sunday. In some of their pass-rush packages, the Broncos played defensive end Robert Ayers opposite Phillips. Ayers finished the game with a sack.
Irving and Ayers would keep similar roles moving forward.
Denver (12-3) closes its regular season against the Oakland Raiders (4-11) and can earn home-field advantage in the AFC with a victory. The Broncos clinched the AFC West and a first-round playoff bye with the win over the Texans.
"People get sick of hearing me say it, but it's next man up, literally," Fox said after the game. "Nate Irving stepped in and did a very good job. Our team has been that way the whole season -- doesn't matter what phase of the game it is, even me taking a leave of absence [heart surgery] for four weeks."
The Broncos were 6-0 when Miller sat out with his suspension this season and 6-3 with him in the lineup.
ESPN NFL Insider Adam Schefter contributed to this report.