Drafted in the long-forgotten 12th round (310th overall) of the 1983 NFL Draft out of Minnesota, Karl Mecklenburg began his professional career as a longshot defensive end before evolving into one of the most uniquely versatile front-seven weapons in football history. Nicknamed the "Albino Rhino," he earned the ultimate reputation as a defensive "Swiss-Army Knife," lining up at all seven front-seven positions—inside linebacker, outside linebacker, nose tackle, and both defensive end spots—often shifting between multiple alignment roles over the course of a single game to attack opposing offenses.

Mecklenburg's career took a major step forward when Denver moved him to inside linebacker, while still utilizing him as an interior pass rusher on third downs. His breakthrough season was in 1985, when he achieved a career-high 13.0 sacks, setting a franchise record at the time, which earned him his first Pro Bowl selection and First-Team All-Pro honors. He confirmed this was no accident in 1986, earning AFC Player of the Year from Football News after recording 9.5 sacks and leading Denver's defense to a Super Bowl XXI appearance.

During his peak from 1985 to 1989, Mecklenburg was the crucial tactical force in Joe Collier's defense. He earned four First-Team All-Pro honors (1985, 1986, 1987, 1989) within five seasons. His 1989 campaign was a showcase of dominance, as he led the Broncos with a personal best of 143 tackles, along with 7.5 sacks and four forced fumbles. He topped the NFL in Approximate Value and helped Denver reach Super Bowl XXIV for the third time in his career.

Despite aging and injuries, Mecklenburg's keen instincts and diagnose-and-attack skills kept him among the league's top linebackers into the early 1990s. He received Pro Bowl nominations again in 1991 and 1993, leading the linebacking unit through scheme changes and remaining one of the most hard-hitting interior defenders. Notably, he is the only player in Denver history to achieve four sacks in a single game twice, showcasing his rare talent for disrupting pass protections from the inside.

Across 12 seasons in Denver (1983–1994), Mecklenburg played 180 games, with 1,145 tackles, 79.0 sacks, 16 forced fumbles, and five interceptions. The Broncos inducted their six-time Pro Bowler into the Ring of Fame in 2001.