During UFC 77, it was announced that Brock Lesnar finally reached a deal to fighting with the Ultimate Fighting Championship (UFC). 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. Lesnar secured an early takedown, but was deducted a point for hitting Mir on the back of the head. After another big takedown by Lesnar, Mir surprisingly managed to secure a submission move and press a submission at 1:30 of the first round. Due to the large size of his hands, Lesnar was wearing 4XL MMA Gloves for the fight, which makes him the second person in Nevada's fight sports history to wear such MMA gloves after Choi Hong-man and also his MMA Shorts were rather large too.
At UFC 82, they announced that the former UFC Champ And UFC Hall of Famer Mark Coleman would fight Lesnar at UFC 87:Seek and Destroy. Coleman was forced to retreat from the fight due to a training combat injury, and Lesnar's adversary was changed to Heath Herring. In the beginning of the first round, Lesnar dropped Herring with a straight right. For the remainder of the fight, Lesnar kept the fight on the ground and went on to win by unanimous decision.
Lesnar's next opponent was Randy Couture for the Heavyweight Championship at UFC 91:Couture vs Lesnar on November 15. Lesnar beat Couture via a tko in Round 2, becoming the UFC Heavyweight Champion.
On December 27, 2008, at UFC 92, Frank Mir thwarted Antnio Rodrigo Nogueira for the Interim Heavyweight title and was to face Lesnar for the Undisputed UFC Heavyweight Championship at UFC 98. straight off after winning the Interim Heavyweight title, Mir looked for Lesnar in the audience and said, "You've got my belt."
However, due to a knee injury to Mir, the title match with Lesnar that was originally slated to be the UFC 98 main event was postponed. The news broke during the broadcast of UFC 96 that the bout had been cancelled and was replaced by Rashad Evans vs. Lyoto Machida for the UFC Light-Heavyweight Championship." Lesnar won the postponed rematch with Mir at UFC 100 on July 11, 2009, via technical knockout after dominating his opposition for the length of the bout. The win earned Lesnar Beatdown of the Year honors from Sherdog for 2009. It's an award he also shares with Anderson Silva after his win over Forrest Griffin.. During his post-match celebration, Lesnar flipped off the crowd who had been booing him for unsportsmanlike behavior including taunting the recovering Frank Mir. The sponsors on his MMA Shorts were also not impressed. He made a derogative remark about the PPV's main sponsor Bud Light, claiming they "won't pay me nothin'", promoting Coors Light instead. He then stated he might even "get on top of his wife" after the show. He would later apologise for his actions in his post-fight conference, where he held a bottle of Bud Light.
In January 2009, Brock Lesnar signed a endorsement deal with Dymatize Nutrition. A CD containing training footage of Lesnar was included with boxes of Dymatize Xpand and Energized Xpand.
On July 1, 2009 it was stated that the winner of the Shane Carwin vs. Cain Velasquez fight at UFC 104 would face Brock Lesnar in his second title defence on a date yet to be determined; however, the UFC then reconsidered the contendership bout and Lesnar was scheduled to defend his belt against Shane Carwin at UFC 106 on November 21. However due to a major illness that just about ended Lesnars life the fight has been postponed to late 2010.