O'Leary battled back to drop Chamberlain after being floored twice in the early rounds, but the hometown hero was dramatically halted in the 10th round of their super-lightweight fight at 3Arena.
Chamberlain had taken a firm grip on the fight from the second round when he floored O'Leary with a left hand.
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O'Leary was on the brink of a swift stoppage loss when he was dropped again in the third, sinking to the canvas after an uppercut from Chamberlain.
Roared on by a vociferous crowd, O'Leary launched a spirited rally and a body shot sent Chamberlain crumpling to the floor by the ropes in the seventh.
O'Leary's pursuit of a comeback win was ruthlessly ended by Chamberlain a few rounds later, though, as the Portsmouth fighter landed a huge right hand that prompted the referee to wave it off.
After his unbeaten record was ended, O'Leary called for a rematch: "I thought I was well back in the fight when it happened but it is what it is.
"Mark was the better man on the night. A fight like that, I think we all want to see a rematch."
Chamberlain, who put his career back on track after a draw with Jack Rafferty last August, said: "I'm not a stranger to an away day, and anyone that knows me deep down knows I will fight anyone, anywhere.
"If it means I've got to go in the champion's back garden, I'll do that.
"But I take my hat off to Pierce because he's a true champion and he'll come again."
