In the summer of 2008, Askren defeated national runner-up Tyrone Lewis in two consecutive matches by decision at the US Olympic Trials in Las Vegas, becoming the second University of Missouri wrestler to qualify for the Olympics. Sammie Henson, who also attended Missouri but finished his college wrestling career at Clemson, competed in the 2000 Olympics winning a silver medal. Askren competed in the 74 kg. weight class at the 2008 Summer Olympics. Askren won his first match via pin against Hungarian István Veréb. In his round of 8 match he lost to Cuba’s Ivan Fundora 1–3, 0–4. The Cuban’s loss to Russia’s Buvaisar Saitiev in the quarterfinal round ended Askren’s hopes of a medal at the 2008 Games.

In college, he wrestled in the 174 lb. weight class. He lost the National Collegiate Athletic Association (NCAA) championship match to Chris Pendleton in both 2004 and 2005 before winning it in 2006 and 2007. He is known for his pinning ability (he holds the single-season NCAA pin record); his massive afro; and his “funky”, or unorthodox, wrestling style. For example, while being ridden in the 2005 championship match, he attempted to reach around and apply a headlock to Pendleton, a move that any wrestling coach would disavow. His tall, lanky body — in sharp contrast to the squat, muscular physiques of many top wrestlers — allows him to attempt moves that most wrestlers could not. This characteristic later led to a challenging transition to freestyle wrestling early in his career, as the freestyle rules differ from folkstyle wrestling and penalize a wrestler for exposing his back. His younger brother Max also wrestled for Missouri and won a national championship in 2010.

Askren finished his collegiate wrestling career with a record of 153–8, with 91 of those victories coming by way of fall. Those 91 pins put him at third on the all-time NCAA Division I pins list. In his four-year career at Missouri, Askren only lost to two opponents, Chris Pendleton of Oklahoma St. and Ryan Lange of Purdue. He was also a four-time All-American, including being only the twelfth Division I wrestler ever to be a four-time finalist. Askren was also nominated for an ESPY in 2007 in the category Best Male College Athlete. On January 9, 2012 it was announced that Askren would be one of six new inductees to the University of Missouri Intercollegiate Athletics Hall of Fame.

Askren made his professional MMA debut on February 7, 2009. It was held by Headhunter Productions at the Holiday Inn Select Executive Center in Columbia, Missouri. He defeated Josh Flowers via TKO early in the first round.

Askren is married and has 3 children. He is also competitive in the sport of disc golf. In 2009, Askren finished 9th in the Amateur World Championships. Askren is sponsored by Discraft. He is also involved in cryptocurrency investing.

Although Askren decided to pursue a career in MMA after the Olympics, he continued to compete in wrestling occasionally. In 2010, he avenged his Olympic loss by defeating Fundora in the semifinals of the Cerro Pelado International, in Cuba. This came shortly after Askren won the Dave Schultz Memorial International. Later in the same year, Askren defeated 2009 world silver medalist Jake Herbert in a folkstyle rules match at the Midlands Tournament. Askren also competed in the Agon Wrestling Championships and the Flo Premier League. In May 2019, Askren lost by technical superiority to Jordan Burroughs in the annual Beat the Streets benefit event.

Askren was a participant in Bellator Fighting Championships Season 2 Welterweight Tournament. In his first fight, Askren defeated Ryan Thomas via technical submission at Bellator 14 on April 15, 2010. The outcome of the fight was controversial because Thomas protested the stoppage as soon as Askren released the choke.

On October 21, 2010 in Philadelphia Askren took on the Bellator Welterweight Champion Lyman Good. Despite being hit with a brutal upkick and almost getting caught in a triangle choke with one minute left, he was able to take down and control Good in every round. Askren won via unanimous decision (49–46, 48–47, and 50–45) to win the Bellator Welterweight Championship.

Askren successfully defended his title against season 5 welterweight tournament winner Douglas Lima at Bellator 64 on April 6, 2012 on Good Friday at the Caesars in Windsor, Canada.

Next for Askren was a title defense against Karl Amoussou, the fight taking place at Bellator 86 on January 24, 2013. Askren once again used his top control wrestling to shut down his opponents grappling, and opened a cut on Amoussou’s forehead with an elbow strike. The doctor stepped in between the third and fourth rounds, judging the cut too severe for Amoussou to continue.

On November 14, 2013, following a negotiation period, Bellator announced they had released Askren from the company, and that he was now an unrestricted free agent.

On December 9, 2013, Askren signed a 2 year/6 fight contract with ONE Championship.

Askren faced Suzuki at ONE Fighting Championship: Reign of Champions on August 29, 2014. He won the fight via TKO due to strikes in the first round to become the new ONE Welterweight Champion.

In the next fight Askren beat Russia’s Nikolay Aleksakhin at the ONE Championship: Global Warriors on April 15, 2016 by unanimous decision.

Askren then fought Agilan Thani at the ONE Championship: Dynasty of Heroes on May 26, 2017. He won the fight via submission due to an arm-triangle choke in the first round.

Askren then faced Zebaztian Kadestam at the ONE Championship: Shanghai on September 7, 2017. He won the fight via TKO due to punches.

In his last fight, Askren faced fellow veteran Shinya Aoki at ONE Championship: Immortal Pursuit on November 24, 2017. Prior to the fight, he claimed this would be his last fight. He won the fight via TKO due to punches in the first round. He retired from MMA after the win.

On November 3, 2018, it was announced that the UFC had signed Askren under the “trade UFC and One Championship agreement”, in exchange for former UFC Flyweight Champion Demetrious Johnson.

Askren made his UFC debut against the former UFC Welterweight Champion Robbie Lawler on March 2, 2019 at UFC 235. The bout was initially scheduled for UFC 233, but after the event was cancelled the fight was rescheduled for UFC 235. Askren won the fight via bulldog choke in the first round, through a controversial stoppage by referee Herb Dean. Lawler appeared unconscious, prompting referee Herb Dean to stop the fight. Immediately after, Lawler stood up protesting the stoppage. Replays appear to show Lawler’s arm going limp and giving a thumbs up right after, which some attribute to Lawler slipping in and out of consciousness. Although controversial, Nevada Athletic Commission executive director Bob Bennett explained that the commission had “no problem” with Dean’s decision to stop the fight.

Askren faced Jorge Masvidal on July 6, 2019 at UFC 239. Askren was violently knocked out with a flying knee 5 seconds into the first round, the fastest knockout in UFC history.

Askren faced Demian Maia on October 26, 2019 at UFC on ESPN+ 20. He lost the fight via submission in round three. This fight earned him the Fight of the Night award.

On November 18, 2019 Askren announced his retirement from mixed martial arts competition.