McGregor (18-2) spent much of the first two rounds on his back, but the Irish sensation finished the fight with a lightning-quick combination. After a huge left hand put Mendes down, McGregor pounded away for the stoppage and then jumped onto the cage in celebration.
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Mendes (17-3), who stepped in for injured featherweight champion Jose Aldo just 2 1/2 weeks ago, embraced McGregor in sportsmanship after a promotion dominated by high-level trash talk.
The Associated Press contributed to this report.