Griffen attended Agua Fria High School in Avondale, Arizona, the same high school as Vikings Hall of Famer Randall McDaniel. At Agua Fria, Griffen played as a defensive lineman and running back. As a junior, he rushed for 794 yards on 142 carries for eight touchdowns, and had 12 receptions for 168 yards and one 71-yard reception where he outraced everybody for a score. On defense, he was double and triple-teamed but still managed 47 tackles, five sacks and three fumble recoveries. In his senior year, 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.) with 20 touchdowns and had 6 receptions with 2 touchdowns as a running back. His 2006 senior season honors included Super Prep Player of the Year, Scout.com Player of the Year, Parade All-American, EA Sports All-American first team, Super Prep All-American, Prep Star All-American, Scout.com All-American, Lemming All-American, Super Prep Elite 50, Prep Star 100, Rivals.com 100, Super Prep All-Farwest, Prep Star All-West, Scout.com All-West, Long Beach Press-Telegram Best in the West first team, Orange County Register Fab 15 first team, Tacoma News-Tribune Western 100 and Gatorade Arizona Player of the Year.
Also a standout track & field athlete, Griffen was one of the state's top performers in the throwing events. At the 2007 4A I State Meet, he won both the shot put and discus events. He recorded top throws of 17.67 meters (58 feet) in the shot put and 55.11 meters (180 feet, 8 inches) in the discus. 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, which earned him the nickname "The Freak" and led to comparisons to All-Pro defensive end Jevon Kearse. Griffen also earned first-team all-region honors in basketball.
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, Joe McKnight, and Chris Galippo. During the recruiting process, he took official visits to USC, Michigan, Notre Dame, Oregon, UCLA, and Florida before eventually committing to the Trojans on November 24, 2006. Griffen reported a 3.3 core GPA and a 1020 SAT score.
Griffen had an impressive showing as a first-year true freshman backup defensive end in 2007, playing primarily in pass rushing situations. Overall, in 2007, while appearing in all 13 games (2 starts), he totaled 21 tackles, including 5.5 for losses of 30 yards (all were sacks), 2 forced fumbles, 1 fumble recovery and 2 pass deflections. He became the first USC true freshman to start an opener on the defensive line in 21 seasons since Tim Ryan in 1986 against Illinois and the first true freshman to start on the defensive line since Shaun Cody did so in 2001 against Utah. In the Trojans' 24–3 victory over Oregon State in week 9, 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. In week 11, he had 6 tackles (with a sack) and a fumble recovery that set up a USC touchdown at Arizona State. For his season efforts in 2007, he was named to the Sporting News Freshman All-American first team, Football Writers Association of America Freshman All-American first team, Rivals.com Freshman All-American first team, Scout.com Freshman All-American first team and Collegefootballnews.com Freshman All-American second team, plus was the Sporting News Pac-10 Defensive Freshman of the Year and was an All-Pac-10 honorable mention pick.
In the fall practice before his freshman season, Griffen and veteran defensive end Kyle Moore got into heated competition that culminated with a fight during practice; the two reconciled and are now friends. During spring practices, former USC coach Pete Carroll staged a prank by having the Los Angeles Police Department enter a team meeting and arrest Griffen for “physically abusing a freshman” (Trojans offensive guard Matt Meyer); Griffen was previously aware of the prank.
In his sophomore year in 2008, Griffen was USC's pass rush specialist as a backup defensive end. He appeared in all 12 games (all but Washington State) and started the first 3 games (Virginia, Ohio State and Oregon State) for the Trojans, compiling 18 tackles, including 6 for losses of 43 yards (with 4.5 sacks for minus 39 yards). He had three tackles against Oregon State and California and 2 versus Virginia, Ohio State, Oregon and Stanford (1.5 for losses). He missed the Washington State game because he was sick.
On July 4, 2009, at a Fourth of July party on Nantucket Island, Griffen and a teammate, linebacker Jordan Campbell, were cited by the Nantucket Police Department for a noise violation; no charges were filed and the two agreed to write a letter of apology.
In 2009, Griffen was second team All Pac-10.
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.
At the 2010 NFL Scouting Combine, Griffen (who measured at 6'4", 278-lb) put on a show, running an electronic-timed 4.66 in the 40-yard dash and bench-pressing 225 lbs 32 times. His 40 time was second among defensive lineman, while his 32 reps were tied for sixth-best. Entering his Pro Day workout as one of the most scrutinized prospects in the NFL Draft, Griffen lived up to his nickname as "The Freak," posting a 34-inch vertical jump, 9-foot-7 broad jump and 40-yard dash time of 4.59 seconds, though some scouts had his second run as low as 4.46.
Griffen was selected by the Minnesota Vikings with the second pick in the fourth round of the 2010 NFL Draft, becoming the 100th player selected overall.
After being inactive for the opening five games of the season, Griffen played in the final 11 games, finishing his rookie year with 11 tackles, all of them solo. He posted a season-high five tackles against the Green Bay Packers in Week 11. On January 28, 2011, Griffen was arrested in Los Angeles for public intoxication. Three days later, he was arrested again after he was found driving with an invalid drivers license. He then tried to flee on foot only to be tased.
In his second season, Griffen played in all 16 games for the Vikings, mostly on special teams as a gunner on punt coverage at times as well as serving as a regular on return units, helping the Vikings special teams unit set a team record with a 26.9 kickoff return average for the season and tied for 1st in the NFL with 4 kickoff returns of +50 yards. His 4.0 sacks on the year ranked 4th on team and contributed to the Vikings 50.0 total sacks on the season, tied for 1st in the NFL. His 18 special teams tackles ranked second on the team behind team-leader Eric Frampton, who posted four more. In Week 2 against the Tampa Bay Buccaneers, he notched his first career sack when he brought down quarterback Josh Freeman.
After a quiet performance early in Griffen's third year as a pro, he came on strong late in the season, posting 5.0 sacks, 1 interception returned for a touchdown and 16 quarterback hurries in the final seven games. His first sack of the year came in week 2 as he brought down Andrew Luck for a 22-yard loss against the Indianapolis Colts. It was the third-longest sack in team history. On October 11, 2012, Griffen was given an indefinite leave from the team after his mother died. In week 15 against the St. Louis Rams, Griffen scored his first career touchdown on his first career interception, taking to the house a Sam Bradford pass 29 yards for the score in a key victory for the Vikings' playoff chances. His 29-yard interception return TD ranks as the 4th-longest in Vikings history by a defensive lineman. The following week, he earned his first career start at Houston, finishing the game with a solo tackle. On December 30, he posted a career-best 3.0 sacks against Green Bay in the regular season finale win over the Packers that gave the Vikings a playoff berth. He had a tackle and a sack in his playoff debut at Green Bay in the 2012 NFC Wild Card game.
In 2013, Griffen was used all over the defensive line, playing in all 16 games with no starts. He finished the 2013 season with 5.5 sacks, including 2.5 in the final 2 games of the regular season. On September 29, he recorded the game-winning strip-sack against the Pittsburgh Steelers in the NFL International Series game at London. In week 2 at Chicago, he tipped a Jay Cutler pass that led to a Kevin Williams interception in the endzone for a touchback. He recorded a season-best 6 tackles and tied a career-high with 3.0 tackles for loss in a loss against the Cincinnati Bengals. He ended the season with 27 tackles (18 solo), 5.5 sacks and a forced fumble.
On March 9, 2014, Griffen re-signed with the Vikings on a five-year contract worth $42.5 million, including $20 million guaranteed. He enjoyed a breakout season in his first year as a full-time starter, helping the Vikings revamped defense have the most improved defense in the NFL. He started all 16 games after entering the season with one start in his first four seasons with the Vikings. On October 19, Griffen had a career day against the Buffalo Bills in week 7 when he recorded a career-high 9 tackles and tied a career-high with 3.0 sacks. He was named NFC Defensive Player of the Month in October after recording 6 sacks and a forced fumble in just four games. In week 13 against the Carolina panthers, Griffen returned a Jasper Brinkley blocked punt for 43 yards for a touchdown, making it the longest blocked punt returned by a Vikings player in franchise history. 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.
On October 18, 2015 Griffen missed the game against the Kansas City Chiefs due to an illness. Griffen was selected as the NFC Defensive Player of the Week for week 17, becoming the third Vikings player to win the NFC Defensive Player of the Week award in 2015, joining nose tackle Linval Joseph and cornerback Terence Newman. In the game, Griffen registered two sacks, including one that forced a fumble by Packers quarterback Aaron Rodgers that Captain Munnerlyn returned 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. Griffen ended his second year as a starter tied for fourth in the NFC and twelfth in the league with 10.5 sacks, becoming the first player in a Mike Zimmer defense ever to record double-digit sacks in back-to-back seasons (he had 12 in 2014). 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.
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. In the Vikings' upset of the 1-1 Carolina Panthers in Week 3, Griffen tied a career-high with 3.0 sacks for losses of a combined 37 yards as the Vikings sacked Cam Newton a total of eight times, which tied the team's third-highest total in a road game and was the most since 2003. On September 28, Griffen was named NFC Defensive Player of the Week, joining John Randle and Chris Doleman as the only Vikings defensive linemans to win a Defensive Player of the Week Award in consecutive seasons. In the Vikings' 31-13 win over the Houston Texans in Week 5, Griffen sacked Brock Osweiler two times, but both sacks were negated due to penalties. Griffin recorded a strip sack of Dak Prescott but the Vikings lost to the Dallas Cowboys. Griffen had a strong performance in the Vikings' 25-16 win over the Jacksonville Jaguars in Week 14; on the Jaguars second possession of the game, Griffen was able to get around the edge and sacked Blake Bortles for a loss of six yards. His second sack of the game came after halftime when he cut back in to the middle and got to Bortles for a six-yard loss. On that same drive, he batted down a ball intended for Jaguars running back Corey Grant. Griffen was ranked 92nd by his peers on the NFL Top 100 Players of 2017.
On July 26, 2017, Griffen signed a four-year, $58 million contract extension with the Vikings through the 2022 season.Longest blocked punt by a Viking for a touchdown (43 yards against the Panthers in 2014)