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In October 2010, the WEC merged with the UFC. As part of the merger, all WEC fighters were transferred to the UFC.
Henderson made his UFC debut at UFC 129. On April 30, 2011, defeating Mark Bocek via unanimous decision.
Henderson next faced Jim Miller. On August 14, 2011. Henderson dominated the streaking Miller throughout the fight, utilizing a stiff jab, great transitions, and vicious ground and pound throughout the match to snap Miller's 7 fight win streak, the third longest in the UFC at the time. Despite being threatened with multiple deep submission attempts, Henderson escaped each attempt and advanced position with increasingly brutal punches and elbows. He earned a unanimous decision (30-27, 29-28, 30-26).
Henderson faced Clay Guida on November 12, 2011. He won the fight via unanimous decision after three rounds in a action packed war that earned both fighters Fight of the Night honors. With the win, he became the #1 contender for the UFC Lightweight Title.
Henderson faced Frank Edgar on February 25, 2012 at UFC 144. Henderson defeated Edgar via unanimous decision to become UFC Lightweight Champion. Henderson left relatively unscathed and outlanded Edgar 100 to 81 in the striking game. Both participants earned Fight of the Night honors for their performance.