Carwin made his UFC debut on the undercard of UFC 84 against Christian Wellisch. He won the match by KO via punch in 44 seconds in the first round, demonstrating his punching power by sending Wellisch’s mouthpiece flying across the octagon. Carwin followed up with an appearance in Birmingham, England at UFC 89 against Neil Wain, winning by TKO in 1:31 of the first round.
At UFC 96, Carwin took a major step up in competition when he faced former number one contender and renowned Brazilian Jiu Jitsuace Gabriel Gonzaga. Carwin scored a knockout via a straight right hand after 69 seconds of the first round.
Carwin was then set to face Cain Velasquez at UFC 104, with the winner getting a title shot against Brock Lesnar; however, the UFC reconsidered the bout and Carwin was confirmed to fight for the title at UFC 106 on November 21, 2009. The fight was later postponed after Lesnar pulled out due to illness, with UFC 108 a likely date. Lesnar then pulled out of that fight on October 26, and Dana White reported at the UFC 105 post-fight press conference that Lesnar was too ill to compete and was expected to be out for the first half of 2010 while recovering from an intestinal disorder and subsequent surgery.
Carwin fought Frank Mir for the UFC Interim Heavyweight Championship on March 27, 2010 at UFC 111. Carwin stated on his website that, “Mir is a legend of the sport, and I would be honored to fight him.” Carwin won the fight in the first round by knockout to become the Interim UFC Heavyweight Champion. The bout also marked the longest fight of Carwin’s career at 3 minutes and 48 seconds; his previous mark was his MMA debut against Carlton Jones, with the time of 2 minutes and 11 seconds. FollowingUFC 111, Beau Dure of USA Today compared Carwin to Mike Tyson, echoing a similar comparison, made prior to the event, by Mark Wayne of Fightline.com.
Carwin then went on to face Brock Lesnar for the UFC Heavyweight Championship at UFC 116. He was able to dominate the first round after knocking Lesnar down and unleashing a relentless ground and pound attack. However, in the second round, Lesnar was able to take Carwin down and apply an Arm Triangle Choke, forcing Carwin to submit.
Carwin was scheduled to face Roy Nelson on January 1, 2011 at UFC 125; however, he later announced on his website that he would pull out of the fight due to back and neck pain, which required surgery that took place on November 2, 2010. Carwin later stated that the neck surgery was a success.
On January 3, 2011, Carwin posted a blog on his website, stating that he had just begun his first day of training since his neck surgery, hoping to be back in the octagon by May or June 2011.
Carwin was expected to face promotional newcomer Jon Olav Einemo on June 11, 2011 at UFC 131. But another bout with diverticulitis sidelined Brock Lesnar, so Carwin agreed to step in to the main event to fight Junior dos Santos for a shot at the UFC heavyweight championship.