"Notorious," who had not earned a win inside the Octagon since 2016, landed with a head-kick and followed with several perfectly-placed shots that floored Cerrone. Referee Herb Dean stepped in just 40 seconds into the welterweight contest to wave it off.
McGregor, who took time off after a loss to Khabib Nurmagomedov for the lightweight title in 2018, appeared to land with a shoulder strike moments into the bout that rattled "Cowboy."
In the co-main event, Holly Holm picked up a decision over Raquel Pennington, as the former champion kept her name on a short list of contenders to UFC bantamweight and featherweight champion Amanda Nunes.
Complete results are below:
* Conor McGregor def. Donald Cerrone via TKO (strikes) at :40 of Round 1
* Holly Holm def. Raquel Pennington via unanimous decision (29-28, 30-27, 30-27)
* Aleksei Oleinik def. Maurice Greene via submission (armbar) at 4:38 of Round 2
* Brian Kelleher def. Ode Osbourne via submission (guillotine choke) at 2:49 of Round 1
* Carlos Diego Ferreira def. Anthony Pettis via submission (neck crank) at 1:46 of Round 2
* Roxanne Modafferi def. Maycee Barber via unanimous decision (30-27, 30-27, 30-26)
* Sodiq Yusuff def. Andre Fili via unanimous decision (29-28, 29-28, 29-28)
* Askar Askarov def. Tim Elliott via unanimous decision (29-28, 30-27, 30-27)
* Drew Dober def. Nasrat Haqparast via TKO (strikes) at 1:10 of Round 1
* Aleksa Camur def. Justin Ledet via unanimous decision (29-28, 30-27, 30-27)
* Sabina Mazo def. JJ Aldrich via split decision (28-29, 29-28, 29-28)