Makhachev's superior grappling skills shone through as he secured a d'arce choke, forcing Poirier to tap in front of a crowd featuring former American president Donald Trump.
The victory marked Makhachev's third successful title defence.
Meanwhile, Poirier hinted at retirement after falling short in what might be his last shot at becoming undisputed champion.
"I know I can compete with the best, but if I do fight again what am I fighting for?" an emotional Poirier said after the loss.
"I've got a little girl that I love. I don’t know, I think this could be it, honestly."
If Poirier does call it quits, he will leave behind a legacy as one of the greatest fighters never to claim an undisputed UFC title.
The pre-fight talk revolved around whether Poirier could finally capture the belt after previous title defeats to Khabib Nurmagomedov and Charles Oliveira.
Poirier boasts an impressive MMA record, winning 21 out of 30 UFC fights since his 2011 debut, including an interim title victory against Max Holloway in 2019.
However, he has always maintained that becoming an undisputed champion was his ultimate goal since stepping into the octagon as a 17-year-old.
Makhachev, however, presented arguably the toughest challenge in the UFC.
Ranked number one pound-for-pound, he held an intimidating 25-1 record heading into the fight.
Elsewhere on the night, Sean Strickland defeated Paulo Costa by split decision in the co-main event and Kevin Holland beat Michal Oleksiejczuk via submission.
