[1] He was selected by the Minnesota Vikings in the fourth round of the 2010 NFL draft and played for them for 10 seasons before signing with the Dallas Cowboys in 2020.

At Agua Fria, Griffen played as a defensive lineman and running back for the Owls high school football team.

As a senior, Griffen recorded 77 tackles, 16 sacks and a fumble recovery as a defensive end and ran for 1,251 yards on 159 carries (7.9 avg.)

[3] Following his junior season, he attended the 2005 Arizona summer camp, where he ran a 4.46-second 40-yard dash at 6-foot-4 and about 260 pounds,[1] which earned him the nickname "the Freak" and led to comparisons to All-Pro defensive end Jevon Kearse.

Following his high school career, Griffen was selected to play in the 2007 U.S. Army All-American Bowl along with fellow USC recruits Marc Tyler, Kristofer O'Dowd, Joe McKnight, and Chris Galippo.

During the recruiting process, he took official visits to USC, Michigan, Notre Dame, Oregon, UCLA, and Florida before committing to the Trojans on November 24, 2006.

[5] Griffen had an impressive showing as a first-year true freshman backup defensive end in 2007, playing primarily in pass rushing situations.

[7] In the Trojans' 24–3 victory over Oregon State on November 3, Griffen posted six tackles and a career-high 3.5 of USC's nine total sacks to earn Rivals.com National Freshman of the Week honors.

[17] After USC's 24–13 victory over Boston College in the 2009 Emerald Bowl, Griffen announced he would forgo his final year of eligibility and enter the 2010 NFL draft.

[18] At the 2010 NFL Scouting Combine, Griffen (who measured at 6'3 3/8", 273-lb) put on a show, running an electronic-timed 4.66 in the 40-yard dash and bench-pressing 225 lbs 32 times.

[31] On December 30, he posted a career-best 3 sacks against the Green Bay in the regular season finale win over the Packers that gave the Vikings a playoff berth.

On September 29, he recorded the game-winning strip-sack on Ben Roethlisberger against the Pittsburgh Steelers in the NFL International Series game at London.

[34] In Week 2 in a road game against the Chicago Bears, he tipped a Jay Cutler pass that led to a Kevin Williams interception in the endzone for a touchback.

[42] Griffen ended his breakout season with 57 combined tackles (41 solo), one forced fumble, one blocked punt for a touchdown, three passes defensed, and a career-best 12 sacks, which led the team and tied for ninth-best in the league.

[45] In the game against the Green Bay Packers, Griffen registered two sacks on Aaron Rodgers, including a strip-sack that was recovered by cornerback Captain Munnerlyn, who returned it for a 55-yard touchdown in the Vikings' 20–13 win; in addition, he also added four quarterback hits and six tackles, three of which were for a loss.

[47] On January 14, Griffen was picked to take the place of Houston's defensive end J. J. Watt in the 2016 NFL Pro Bowl, marking his first career invitation to the annual showcase game in Hawaii.

[48] On September 18, Minnesota opened their new stadium with a win against division rival Green Bay Packers and Griffen contributed with a sack and a forced fumble.

[56] In the Vikings' Divisional Playoff game against the New Orleans Saints, Griffen tipped a Drew Brees pass that ended up being intercepted by teammate Anthony Barr.

His arrival generated a great expectation that he could be part of a formidable pass-rushing unit along with defensive ends DeMarcus Lawrence, Aldon Smith and Randy Gregory.

In Week 2 against the Atlanta Falcons, Griffen recorded his first sack with the Cowboys on Matt Ryan late in the fourth quarter to help the team rally from a nine-point deficit and win 40–39.

[69] On October 27, because of the struggles experienced by the defense as a unit, he was moved as part of a roster purge that included free agency acquisitions Dontari Poe and Daryl Worley.

On October 27, 2020, the Cowboys traded Griffen to the Lions in exchange for a conditional sixth-round pick (#192-Quinton Bohanna) in the 2021 NFL draft.

[78] On November 26, Griffen was placed on the non-football illness list under dealing with a personal mental health issue earlier in the week.

[81] On Thursday, September 20, 2018, Griffen and his agent were sent a letter from the Minnesota Vikings, stating that he would not be allowed back with the team until he underwent a mental health evaluation.

[82] Two days later, on Saturday, September 22, Griffen was involved in an incident at Hotel Ivy where he had allegedly threatened to shoot someone because he was not allowed in his room.

[89] In his plea deal for his second petty misdemeanor conviction, Griffen had his driver's license revoked and was ordered to commit no alcohol-related or careless driving offenses.