Victory came after the horse's hugely disappointing display when sent off favourite last month in another English Classics race, the 2,000 Guineas at Newmarket.
But Auguste Rodin, ridden by Ryan Moore, returned to his best form at Epsom, overhauling 66-1 outsider King of Steel in the closing strides.
White Birch ran on for third with Artistic Star taking fourth.
Moore hailed Irish trainer O'Brien's work in reviving Auguste Rodin's fortunes by telling ITV Sport: "He's the only man that could do it.
"I've seen him get horses back. There's been horses that have run bad in the Guineas and have come back. Roderic O'Connor springs to mind and a few others, even Qualify ran bad in a Guineas and came and won an Oaks. Aidan can just do things."
Moore added: "This horse has a great pedigree, he's always shown he's a good horse.
"As Aidan says, everyone does such a good job at home and everything went smooth today."
The result meant jockey Frankie Dettori, riding Arrest, was denied victory in his final Derby before retirement.
There had been concerns the Derby, the premier race of the English flat season, would be targeted by animal rights activists and police did make two arrests during the race itself.
One protester did make it onto the track but was held before the horses reached that part of the course.
Earlier Saturday, police arrested 19 people ahead of the race after the rights group Animal Rising vowed to defy a court injunction and disrupt the blue-riband event.
Surrey Police reported the arrests in areas around the Epsom racecourse, near London, in the hours building up to one of British sport's highest-profile fixtures.
