During UFC 77 on October 20, Lesnar joined Ultimate Fighting Championship with a one-fight contract. On February 2, 2008, Lesnar made his debut with the promotion in an event titled UFC 81: Breaking Point against former UFC Heavyweight Champion Frank Mir. Due to his large hands, Lesnar was wearing 4XL gloves for the fight, making him the second man in Nevada's combat sports history to wear such gloves, after Choi Hong-man. Lesnar secured an early takedown and began landing numerous punches, but was docked a point after a punch hit Mir on the back of the head. He scored another takedown and continued landing ground and pound, before Mir secured a kneebar and forced a submission at 1:30 of the first round.
Despite losing his debut, he was offered a new contract and at UFC 82 on March 1, former UFC Heavyweight Champion and Hall of Famer Mark Coleman was announced to fight Lesnar at UFC 87. Coleman withdrew from the fight due to an injury and was replaced by Heath Herring. In the first round Lesnar scored an early knockdown and went on to dominate the fight winning via unanimous decision by 30-26 on all three judges' scorecards.
Lesnar then faced Randy Couture for the UFC Heavyweight Championship at UFC 91 on November 15. He denied Couture's takedown attempts and outstruck him on the feet, eventually knocking him down and landing ground and pound until he was awarded the technical knockout and UFC Heavyweight Championship.