In 2006 Mousasi signed with Pride FC to take part in Pride’s Welterweight Grand Prix. In the opening round Mousasi faced Makoto Takimoto, at Pride Bushido 11, beating the Japanese fighter by TKO as the result of a broken eye socket in the first round. In the quarterfinals Mousasi went on to face Akihiro Gono, but was submitted in the second round by an armbar. After losing to Gono, Mousasi fought Hector Lombard in the Grand Prix Alternate bout and took a unanimous decision victory over the Cuban-born fighter.

On November 21, 2008, ADCC Europe president Marko Leistén confirmed the signing of Mousasi as one of 2009’s ADCC Championships. It was rumored he would fight in the -88 kg category. For unknown reasons, Mousasi never participated in the ADCC 2009 Championships.

In somewhat of a surprise to the MMA world, Mousasi agreed to take on Japanese K-1 fighter Musashi in a K-1 rules fight at Dynamite!! 2008. Being an open weight fight Mousasi weighed in at 97.8 kg/216 lb, all but confirming his desire to move up in weight classes. Mousasi stated after winning the Dream Middleweight Grand Prix he would no longer fight at middleweight due to the large weight cut. Mousasi was the rank outsider to win the match against the more experienced Musashi, but came out fast and scored a first-round KO. Mousasi went undefeated in 2008, going 6–0 in MMA and 1–0 in K-1.

Mousasi was set to fight Renato “Babalu” Sobral at Affliction: Trilogy on August 1, 2009, but the event was cancelled after losing its main event 10 days prior to the event. It was originally planned for him to face Vitor Belfort at that event, but there was a disagreement between both fighters over which weight class the fight would be fought at.

Mousasi would go on to win his second Strikeforce bout by TKO (punches), three minutes and forty-three seconds into the 2nd round against Rameau Thierry Sokoudjou, who Mousasi was previously supposed to fight at Dream 11, on November 7, 2009 at Strikeforce: Fedor vs. Rogers. Mousasi was originally slated to defend his Strikeforce Light Heavyweight Championship, but eventually competed in a non-title bout.

In February 2010, Mousasi left M-1 Global Management. Mousasi was quoted as saying “After careful consideration, I have decided that it is in my best interest to part ways with M-1 Global,” Mousasi wrote in the e-mail. “During the time I spent under their wing, M-1 Global, as a promoter and management company, allowed me to achieve many great things. I appreciate all they have done for me. My management is being taken care of by someone close to me.”

On April 17, 2010, Mousasi lost the Strikeforce Light Heavyweight Championship belt in his first defense to Muhammed “Mo” Lawal by way of unanimous judge’s decision. Lawal landed 11 of 14 takedowns, however Mousasi had outlanded Lawal in Total Punches 171 to 125. Mousasi was also given a point deduction following an illegal up-kick. Lawal would later test positive for anabolic steroids following a fight with Lorenz Larkin.

Mousasi was expected to face Mike Kyle on April 9, 2011 at Strikeforce 33. However, Kyle was forced off the card with an injury and was replaced by Keith Jardine. The fight resulted in a majority draw (29–27 Mousasi, 28–28, and 28–28), due to an illegal upkick in the first round which resulted in a point deduction for Mousasi. Otherwise the bout would’ve been a unanimous decision victory for Mousasi. According to Fightmetric statistics, Mousasi outstruck Jardine 146 to 21. After the fight in an interview with Ariel Helwani of MMA Fighting.com, Strikeforce CEO Scott Coker stated “I’ve got a lot of respect for Keith Jardine, but I think Gegard won the fight.” In the same interview, Coker also stated that a rematch between Mousasi and Jardine was definitely a possibility for the future. MMA Fighting.com named this fight their Runner-Up for “Robbery of the Half-Year.”

Mousasi returned to Strikeforce to face Ovince Saint Preux on December 17, 2011 at Strikeforce: Melendez vs. Masvidal. He won the fight via unanimous decision, showing improved takedown defense and wrestling.

It was revealed on January 31, 2011 that Mousasi was considering trying out for the 2012 Summer Olympics at the category of boxing. Mousasi would try to qualify himself through Netherlands qualifiers. His management said that it would make him a better fighter. Mousasi is already known in amateur boxing, being a former Netherlands amateur boxing champion.

Mousasi faced Mike Kyle at Strikeforce: Marquardt vs. Saffiedine on January 12, 2013. After avoiding most of Kyle’s strikes in the early going, Mousasi took the fight to the ground and went on to finish the fight via rear-naked choke submission late in the first round. This was the fourth time a fight between Mousasi and Kyle was scheduled and the first time it wasn’t canceled.

On January 15, 2013, the UFC announced Mousasi would be joining 19 other Strikeforce fighters in a move to the UFC after his win over Mike Kyle at the promotion’s last event, Strikeforce: Marquardt vs Saffiedine.

Mousasi was expected to make his promotional debut against Alexander Gustafsson on April 6, 2013 at UFC on Fuel TV 9. However, on March 30, Gustafsson suffered a cut in training and, on April 2, was deemed unclear to participate by the Swedish MMA Federation. Gustafsson was replaced by Ilir Latifi, a UFC newcomer and training partner of Gustafsson. Mousasi won by unanimous decision, avoiding his opponent’s takedown attempts and dominating the fight on the feet. He fought with an injured knee and underwent surgery after the fight. UFC President Dana White praised Mousasi for going through with the fight injured and in his opponents home, as well as accepting a late change of opponents.

For his second fight with the promotion, Mousasi moved down to Middleweight to face former UFC Light Heavyweight Champion Lyoto Machida on February 15, 2014 in the main event at UFC Fight Night 36. He lost the fight via unanimous decision. Despite the loss on his record, the bout won Mousasi his first Fight of the Night bonus award.

Mousasi faced Mark Muñoz on May 31, 2014 in the main event at UFC Fight Night 41. He won the fight via submission in the first round and became the first fighter to submit Muñoz. The win also earned Mousasi his first Performance of the Night bonus award.

Mousasi was expected to rematch Ronaldo Souza on August 2, 2014 at UFC 176. However, after UFC 176, was cancelled, Mousasi/Souza was rescheduled and took place on September 5, 2014 at UFC Fight Night 50. Souza defeated Mousasi via submission in the third round.

Mousasi faced Dan Henderson on January 24, 2015 in the co-main event at UFC on Fox 14. He won the fight via TKO in the first round. The win also earned Mousasi his second Performance of the Night bonus award.

Mousasi faced Costas Philippou on May 16, 2015 at UFC Fight Night 66. He won the fight by unanimous decision.

Mousasi was expected to face Roan Carneiro on September 27, 2015 at UFC Fight Night 75. However, Carneiro pulled out due to injury and was subsequently replaced by Uriah Hall. After dominating the opening round, Mousasi was finished early in the second after absorbing a jumping spinning back kick, flying knee and follow-up punches.

Mousasi was briefly linked to a fight with Michael Bisping on February 27, 2016 at UFC Fight Night 84. However, on December 24, 2015, Bisping was pulled from the bout in favor of a matchup with Anderson Silva at the same event. Mousasi instead faced Thales Leites. He won the fight via unanimous decision.

Mousasi was expected to face Derek Brunson on July 9, 2016 at UFC 200. It was later revealed that Brunson was forced to pull out of the fight, and that Thiago Santos would replace him to fight Mousasi. He won the fight via TKO in the first round and was awarded a Performance of the Night bonus.

A long-discussed fight with Vitor Belfort took place on October 8, 2016 at UFC 204. Mousasi won the fight via TKO in the second round.

Mousasi next faced Uriah Hall in a rematch on November 19, 2016 at UFC Fight Night 99. After mauling Uriah Hall he won the fight via TKO in the first round.

Mousasi faced Chris Weidman at UFC 210 on April 8, 2017. In the second round, Mousasi hit Weidman with two knees to the head, the latter of which had referee Dan Miragliotta interrupt the fight because he mistakenly thought it was illegal. However, upon consultation with another referee “Big” John McCarthy, both knees appeared to be legal under the new unified rules introduced since 2017. Ultimately, the bout was ended and deemed a TKO win for Mousasi. Mousasi accused Weidman of trying to win the fight by disqualification. Weidman admitted he was expecting to win the fight by disqualification. He was only willing to continue when told the knee was legal after almost two minutes of the allotted five to recover by Miragliotta under the assumption the knee was illegal. Audio from Weidman’s corner revealed Matt Serra saying Weidman told physicians he thought it was February. Being unable to tell medical staff the correct date possibly influenced their decision not to let him continue. The NYSAC released a statement that instant replay had been used legally to determine if the knee was legal, disproving the claim of UFC Vice President of Regulatory Affairs Marc Ratner who had told Joe Rogan otherwise on the live pay-per-view.

On 10 July 2017, Mousasi announced that he had signed with Bellator MMA for a six-fights deal and should compete for the middleweight title later in 2017. He also announced that his goal would be also to obtain the light heavyweight belt as well, after becoming the Bellator middleweight champion first.

During the Bellator 181 main card, it was announced by the promotion that Mousasi would make his debut against Alexander Shlemenko at Bellator 185 on 20 October 2017. In the opening minute a punch from Shlemenko broke Mousasi’s right orbital, causing Mousasi to fight with one eye for almost the entire bout. The rest of the first round mainly consisted of Mousasi scoring multiple takedowns, landing many strikes, and attempting several neck cranks and rear naked chokes. A doctor inspected Mousasi’s eye before the second round and deemed him fit to continue. In the second round, both fighters landed strikes in short exchanges for the first three minutes until Mousasi landed two takedowns and spent most of the last two minutes making submission attempts and landing strikes, which caused Shlemenko’s face to bleed. When the round ended, Mousasi was still in a back mount dominant position over Shlemenko. In the third and final round, Schlemenko landed the better of strikes standing up and Mousasi’s only takedown attempt was unsuccessful. Mousasi won the fight via unanimous decision. Seven out of eleven MMA media outlets scored the fight as a decision win for Shlemenko.

Mousasi faced Rafael Carvalho on 25 May 2018 at Bellator 200 in London, England for the Bellator Middleweight World Championship. After scoring a takedown early, Mousasi used ground and pound to win the fight via TKO in the first round. Mousasi became the first fighter to win a world title in both Strikeforce and Bellator MMA.

Mousasi made his first title defense against current Bellator Welterweight Champion Rory MacDonald on 29 September 2018 at Bellator 206. Mousasi stuffed MacDonald’s takedown attempt and delivered ground and pound, eventually winning the fight via technical knockout in round two.

Mousasi was expected to make his second title defense against Rafael Lovato Jr. in the co-headliner of Bellator 214 on 26 January 2019. However, on 20 December 2018, it was reported that Mousasi pulled from the fight, citing a back injury. The fight eventually took place at Bellator 223 on 22 June 2019. Mousasi lost the bout and his title by majority decision.

After, losing the title, Mousasi rematched prior UFC opponent Lyoto Machida at Bellator 228 on 28 September 2019. He was victorious by way of split decision.

In February 2020, it was announced that Rafael Lovato Jr. was forced to relinquish the Bellator Middleweight World title due to a cerebral cavernoma. Bellator then announced that Mousasi would face current Bellator Welterweight World champion Douglas Lima for the vacant Middleweight title at Bellator 242 on 9 May 2020. However, it was announced that Bellator 242 and Mousasi’s fight against Lima would be postponed due to the COVID-19 pandemic. Mousasi’s bout against Lima was rescheduled to take place at Bellator 250. Mousasi won the fight via unanimous decision and claimed the Bellator Middleweight Championship for a second time.