Miller played college football for the Texas A&M Aggies, where he earned consensus All-American honors and the Butkus Award.

In 2021, Miller was traded to the Los Angeles Rams and was a member of the team that won Super Bowl LVI.

In spring 2008, newly hired head coach Mike Sherman was discouraged by Miller's habits of skipping class and failing to produce during practice.

His role was more confined to pass coverage, as opposed to rushing the quarterback, thus he was not able to showcase his pass-rushing abilities.

[11][12] As a junior in 2009, Miller adopted the role of the jack position, a defensive end/linebacker hybrid, which allowed him to use his pass-rushing abilities.

[23] He received first-team All-American honors from Walter Camp, Scout.com, Pro Football Weekly,[24] ESPN.com[25] and the Associated Press.

[33] In March 2011, Miller was selected to represent top-flight rookies in the NFL Labor Union talks.

Former Broncos quarterback John Elway, who is also the executive vice president of the franchise, said Miller is "a type of guy that comes around every 10 years".

He wore number 58 in honor of Pro Football Hall of Fame linebacker Derrick Thomas.

[54] Miller finished the season third in sacks with 18+1⁄2, breaking a Denver Broncos record of 17 previously held by Elvis Dumervil.

[55] In the Divisional Round of the playoffs, Miller had nine total tackles and two quarterback hits in the 38–35 2OT loss to the Baltimore Ravens.

Each time he performed the dance during a game, Ubisoft made a charitable donation to Von's Vision, a foundation devoted to providing eye care and glasses to underprivileged youth.

[58] In July 2013, ESPN reported that Miller had been suspended four games for violating league policy, pending appeal.

He did fairly well upon his return, but his season was ended prematurely when he suffered an anterior cruciate ligament injury (ACL) on December 22, 2013, during a win on the road at the Houston Texans.

[70] Overall, in the 2015 season, Miller finished with 11 sacks, 35 total tackles, 32 quarterback hits, one pass defended, and four forced fumbles.

[72] During the AFC Championship against the Patriots, Miller sacked Tom Brady 2+1⁄2 times, breaking a Broncos single-game playoff record and also had an interception in the second quarter of the game.

Miller recorded six tackles, a pass defended, 2+1⁄2 sacks, two forced fumbles, and two quarterback hurries, and was named Super Bowl MVP for his performance.

[104] During practice on September 8, 2020, Miller suffered what was called a "freak injury near the ankle", and season-ending surgery was feared to be required.

An MRI the next day revealed that the injury was a dislocated peroneal tendon, and Miller was subsequently placed on injured reserve.

[112] At the time of the trade, Miller was the longest-tenured Bronco, and the only remaining nonspecial-teams player from Denver's Super Bowl 50 roster.

In an emotional interview following his trade, Miller held back tears, saying, "I love Broncos Country.

[115] In week 15, a 20–10 home win against Seattle, Miller notched his first sack as a Ram against Seahawks quarterback Russell Wilson.

[118] Overall in the 2021 season, Miller recorded 50 tackles, 9+1⁄2 sacks, one pass defended, and one forced fumble in 15 games played.

[132] Miller struggled after returning from his ACL injury and fell behind other Bills edge rushers on the depth chart during the season.

[134] He also added two combined tackles during the Bills' playoff run, which ended in the AFC Divisional Round when the team lost to the Kansas City Chiefs by a final score of 27–24.

[135] In October, Miller was given a four-game suspension without pay for violating the NFL's personal conduct policy.

[138] In the Divisional Round against the Baltimore Ravens, Miller recovered a fumble forced by Damar Hamlin and returned it 39 yards to help set up the Bills on an eventual touchdown score in the 27–25 win.

[150] In April 2018, while on a guided fishing tour off the coast of Florida, Miller is alleged to have illegally landed and improperly caught and released a hammerhead shark.

[151] On November 30, 2023, the Dallas Police Department issued an arrest warrant for Miller, alleging that he assaulted a pregnant woman.

[152] Multiple police sources claimed that the pregnant woman who accused him of assaulting her was in fact his girlfriend and that the incident happened at their home in Dallas on November 29, 2023.