Warrington attacked the Belfast fighter from the first bell and dominated him for much of an outstanding contest to earn a unanimous decision and keep the belt he won from Lee Selby in May.
Frampton found himself in desperate trouble during the opening two rounds, clinging on bravely after choosing to trade with Warrington but coming off second-best.
Frampton, 31, was attempting to regain a world title for the first time since losing the WBA’s belt to Leo Santa Cruz last year but he was made to look his age by Warrington and struggled to cope with the weight of the Leeds’ fighter’s punches.
Warrington continued to score with flurries through the middle rounds and opened up a small cut under Frampton’s left eye in the third.
Frampton, who had lost just once in 27 bouts prior to the clash in Manchester, fought back to close the score in the eighth and ninth rounds but Warrington turned the screw as the final bell approached, securing his first defence.
The pair hugged at the final bell in a show of appreciation and Warrington took the decision with a score of 116-112 on two cards and a score of 116-113 on the third.
Warrington said: “It takes two to make a fight. I’ve always been a fan of Carl’s and to shake my hand like he did after the fight shows what a sportsman he is. He’ll go down as one of the best.
“There were times when I hit him with some corking shots. Hopefully know I can take this on and go on and unify. I just want to be part of big fights and Oscar Valdez excites me.”
Frampton, a former two-weight world title holder, accepted defeat gracefully afterwards, saying: “No excuses from me, I was incredible shape coming into this fight but the better man won. Josh was fitter and stronger, that’s the bottom line.
“Whoever said Josh can’t punch, I don’t know what they are talking about. He’s even better than I thought. He’s clever, he’s strong, tough and he can punch hard.