The two-division Ultimate Fighting Championship (UFC) World Champion said his fighting days were over in a Twitter message posted on his verified account, alongside a picture of the Irishman with his mother, Margaret.
"Hey guys I've decided to retire from fighting. Thank you all for the amazing memories! What a ride it's been!" he wrote.
"Here is a picture of myself and my mother in Las Vegas post one of my World title wins! Pick the home of your dreams Mags I love you! Whatever you desire it's yours."
The controversial fighter, nicknamed "The Notorious", first announced his retirement from the sport in March last year after being battered into submission by arch-rival Khabib Nurmagomedov in October 2018.
He made a return to the octagon in January after 15 months of inaction to knock out American Donald "Cowboy" Cerrone in just 40 seconds in Las Vegas.
The 31-year-old, an icon of the UFC, is no stranger to controversy and hit the headlines last year for an attack on an older man in a Dublin bar that was captured in a viral video.
McGregor, one of the most popular fighters in MMA history, has a record of 22-4 and was the first UFC fighter to hold two championship belts at the same time.
He achieved that feat in 2016, when he stopped Eddie Alvarez in a lightweight title fight, adding it to his featherweight title.
That triumph was followed by a loss to boxing great Floyd Mayweather in a cross-combat superfight in 2017, his loss to Nurmagomedov, announcements of retirements and returns to fighting.