McGregor came out of retirement for a third time to face fellow 32-year-old Poirier at Abu Dhabi's Fight Island.
And although the Irishman edged the first round, Poirier unleashed a flurry of punches to seal a technical knockout two minutes 32 seconds into round two.
"I'm gutted, it's a tough one to swallow," said McGregor.
"I felt stronger than him, but his leg kicks were good. I didn't adjust. My leg was badly compromised, I've never experienced those low calf kicks, and I wasn't as comfortable as I needed to be.