It was jockey Ryan Moore's second win in the race, having ridden O'Brien's previous winner Gleneagles, in 2015.
Barney Roy (7-2) was second ahead of third-favourite Al Wukair (11-2) in the first Classic of the 2017 Flat season.
Frankel's offspring Dream Castle and Colts Eminent were fifth and sixth respectively over the mile distance.
The 1,000 Guineas, for fillies, takes place at Newmarket on Sunday at 15:35 BST.
Churchill, last season's champion two-year-old, was sitting third at the halfway stage and managed to get the first run on his main rivals as he won by a length from Barney Roy.
Moore said Churchill, who was making his three-year-old debut at Newmarket, had "everything you want in a racehorse".
"He has a magnificent mind, he travels, has speed and loads of class," Moore told ITV Racing. "He was always racing comfortably - he was there a little bit early.
"He always feels like there's more when you ask him."
O'Brien added: "I was very worried about it being his first run. He's a big horse and we knew he would come on for the run. Ryan gave him a lovely ride.
"Everyone at home was very happy with the horse which is why we took the chance to come first time, so I'm delighted."
BBC racing correspondent Cornelius Lysaght
Am I the only one to feel a slight sense of anti-climax?
Obviously, Aidan O'Brien's latest record-breaking feat is a testament to the prolific skills and brilliance of himself, the rest of the Coolmore team, and, of course, of champion stallion Galileo, Churchill's father.
But as a race, I'm not sure. It was hardly the potentially epic showdown billed; the time wasn't great, and the first seven finished within about three lengths.
Churchill was good rather than sparkling, though it was his first run of the season. A word for Barney Roy who stumbled at a crucial moment late on.
Churchill, the 6-4 favourite, won the 2,000 Guineas at Newmarket to give trainer Aidan O'Brien a record-breaking eighth win in the Classic.