Holloway made his promotional debut as an injury replacement for Ricardo Lamas at UFC 143 on February 4, 2012 against Dustin Poirier. He lost the fight via submission (mounted triangle armbar) in the first round.
In his second fight, Holloway faced Pat Schilling on June 1, 2012 at The Ultimate Fighter 15 Finale. After a dominant performance where he almost finished Schilling several times, Holloway won via unanimous decision (30-27, 30-27, 30-27).
Holloway defeated Justin Lawrence, on August 11, 2012 at UFC 150. Holloway won the fight via TKO in the second round after dropping and finishing Lawrence with a knee and punches to the body.
Holloway fought Leonard Garcia on December 29, 2012 at UFC 155, replacing an injured Cody McKenzie. Holloway won the close fight via split decision.
Holloway faced Dennis Bermudez on May 25, 2013 at UFC 160. He lost the fight via split decision.
Holloway faced Conor McGregor on August 17, 2013 at UFC Fight Night 26, replacing Andy Ogle. He lost the fight via unanimous decision, losing to McGregor both in the stand-up and on the ground.
Holloway faced promotional newcomer Will Chope on January 4, 2014 at UFC Fight Night 34. He won the fight via TKO in the second round. The win also earned Holloway his first Knockout of the Night bonus.
Holloway faced Andre Fili on April 26, 2014 at UFC 172. He won the back-and-forth fight via submission in the third round.