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.

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 quickly defeated journeyman Gary Goodridge under MMA rules at Dynamite!! 2009.

After a lot of speculation about Mousasi's opponent for 2010 New Year's Eve, Mousasi was set to face Kyotaro, the K-1 Heavyweight Champion, in a K-1 rules bout. He brought the fight to Kyotaro and in the second round Mousasi knocked the Japanese fighter down, almost finishing him. Mousasi then won a unanimous decision victory from the judges.

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 was later recovering from knee surgery following a torn ACL and was expected to fully recover by November, 2012. He also signed a new contract for six more fights with the organization, making a total of seven. However, with Strikeforce having shut down, this contract was likely now null and void.

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 (30-27, 30-27, 30-27), 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.

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 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 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.

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 October 20, 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 with the scorecard of 29-28, 29-28 and 29-28. Seven out of eleven MMA media outlets scored the fight as a decision win for Shlemenko.