Ryan Clady tore his left ACL during practice on Wednesday and will likely miss the entire 2015 season.
Clady was injured while blocking on a pass play during an 11-on-11 drill. He was treated by trainers after he went down and did not participate for the rest of the practice, but he remained on the field, limping slightly.
"He pulled himself out (of drills), said his knee was sore," Broncos coach Gary Kubiak said. "We really weren't that worried last night, everybody felt good, but we felt like we'd take a look at it this morning, and unfortunately we got some horrible news."
Clady previously blew out his left knee in a pickup basketball game in April 2010, but returned to start every game for Denver that season.
This will be his fourth major surgery in the last five years, with the others coming on his left knee, shoulder and foot.
A first-round pick in 2008, Clady is the last remaining player from Mike Shanahan's 14-year tenure as Broncos coach.
A four-time Pro Bowler and two-time first-team All-Pro, Clady has started 16 games in six of his seven NFL seasons.