In 2009, he became pro and engaged in regional promotional fights, mainly in Louisiana and the Southern United States. In no time, he accumulated a 7-0 record.
His debut in the mixed martial arts (MMA) promotion ‘World Extreme Cagefighting’ (WEC) happened at the WEC 50 event on August 18, 2010, in Las Vegas, Nevada, USA. The event saw him losing to Danny Castillo by a unanimous decision.
The WEC 52 event held after a couple of months on November 12, 2010, saw Poirier beat Zach Micklewright in the first round via TKO.
The merger of WEC with ‘Ultimate Fighting Championship’ (UFC) in October 2010 led to the transfer of all WEC fighters to the UFC.
Post the merger, Poirier got an opportunity to make his featherweight debut at the UFC 125 event. When Jose Aldo, the newly crowned UFC featherweight champion, had to step out from his first title defense against the No. 1 contender Josh Grispi due to a back injury, Poirier took his place in the bout. The event was held in Las Vegas, Nevada on January 1, 2011 and concluded with Poirier winning the fight through a unanimous decision.
The 2011 mixed martial arts documentary ‘Fightville,’ which examines the scene behind this full-contact combat sport in southern Louisiana, featured his interview among the interviews of other fighters and coaches.
The UFC 131 event saw him beating promotional newcomer Jason Young through unanimous decision on June 11, 2011. Young had replaced Rani Yahya in the bout due to the latter’s injury.
Poirier continued his winning spree and went on to beat Pablo Garza at the UFC on Fox 1 via submission (D'Arce choke). The event was held on November 12, 2011, in Anaheim, California, US.
His next win was against Jerome-Max Holloway at the UFC 143 event, held on February 4, 2012, in Las Vegas, Nevada. He won by submission via a mounted triangle armbar that earned him the UFC bonus award ‘Submission of the Night.’
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One of the most notable fights of his career so far is the one with Chan Sung Jung in the main event at UFC on ‘Fuel TV: Korean Zombie vs. Poirier,’ held on May 15, 2012, in Fairfax, Virginia, US.
Although he lost the fight to Jung via submission (D'arce choke), the bout that marked his first main event earned him the ‘Fight of the Night’ honor along with Jung. The bout also garnered honor as ‘Fight of the Year’ from the likes of ‘ESPN MMA Awards,’ ‘Wrestling Observer Newsletter,’ and ‘Sherdog Awards.’
Following the loss, he left ‘Gladiators Academy’ and joined ‘American Top Team’ (ATT).
At ‘The Ultimate Fighter 16 Finale’ on December 15, 2012, in Las Vegas, Nevada, he defeated Jonathan Brookins in the first round by submission (D'Arce choke).
He replaced Dennis Siver due to the latter’s injury to face Cub Swanson in UFC’s co-main event on ‘Fuel TV: Barao vs. McDonald,’ held in London, England, on February 16, 2013. He lost the match via unanimous decision.
On August 31, 2013, in Milwaukee, Wisconsin, US, at the UFC 164, he defeated Erik Koch and then went on to beat Diego Brandão at UFC 168, held on December 28, 2013, in Las Vegas, Nevada.
He wanted a rematch against Swanson and told Canadian MMA journalist Ariel Helwani that Swanson must "be a man."
He earned his second ‘Fight of the Night’ bonus award, fighting and winning against Akira Corassani at ‘The Ultimate Fighter Nations Finale,’ held on April 16, 2014, in Quebec City, Quebec, Canada.
Following his loss to Conor McGregor at UFC 178 on September 27, 2014, in Las Vegas, Nevada, he returned to the lightweight division. Talking about his decision of not returning to featherweight or trying his hand at welterweight, he said in an interview “This is the division (lightweight) I'm going to win the belt at.”
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Twice he earned ‘Performance of the Night’ bonus award, first at UFC Fight Night 63 on April 4, 2015 after beating Carlos Diego Ferreira and second at UFC Fight Night 68 on June 6, 2015 after defeating Yancy Medeiros.
After winning against Joseph Duffy and Bobby Green on January 2, 2016, at UFC 195 and on June 4, 2016 at UFC 199, respectively, he lost to Michael Johnson at UFC Fight Night 94 on September 17, 2016.
He earned his third ‘Fight of the Night’ bonus award after challenging and winning a bout against Jim Miller on February 11, 2017 at UFC 208. He however, had to face indefinite suspension due to the injuries he sustained at the bout.
At the UFC 211, held on May 13, 2017, referee Herb Dean called the bout between Poirier and Eddie Alvarez a ‘No Contest’ as Alvarez landed illegal knees to Poirier's head.
At UFC Fight Night 120 event, held on November 11, 2017, he defeated Anthony Pettis.
On April 14, 2018, Poirier fought against Justin Gaethje at UFC on Fox 29. He won the fight via TKO in the fourth round. This fight earned him the ‘Fight of the Night’ bonus award.
Poirier won his fight against Eddie Alvarez on July 28, 2018, in the main event of UFC on Fox 30. His performance earned him the ‘Performance of the Night’ award.
He won the fight against Max Holloway for the ‘Interim UFC Lightweight Championship’ at UFC 236 on April 13, 2019, for which he received the ‘Fight of the Night’ award. The same year, he faced Khabib Nurmagomedov in a title unification bout at UFC 242 in which he lost the fight via rear-naked choke submission in the third round.