Making the third defence of his IBF title, he also became the WBA champion after recovering from the first knockdown of his career to impressively win at Wembley Stadium.
In only his 19th professional match-up and in front of an estimated 90,000-strong crowd, a post-war record for a fight in the UK, he was at severe risk of his first ever defeat after hitting the canvas in the sixth following a huge right hand.
A period of survival followed before, as he recovered his confidence and ambition in the final rounds, he secured two further knockdowns and forced referee David Fields to intervene with Klitschko unable to defend himself from another heavy barrage.
Since winning his gold medal at the London Olympics in 2012, Joshua has long been seen as the fighter to revive the heavyweight division that had become so predictable during the Klitschkos' lengthy reign.
The biggest questions about his ability to do so focused on whether he truly justified that billing - if he was more than just a promising athlete - and whether the timing was right to test him against perhaps the world's best.
After the competitive opening rounds when each fighter landed promising punches, it was in the fifth when there seemed little that could stop him.
He rocked Klitschko with a big left hand, but after leaving him clinging on and celebrating when sending him to the canvas with a powerful barrage, he became reckless, and swallowed a left hook that then left him fighting to survive.
Suddenly Joshua was the stationary target, looking tired and naive, and from the sixth round Klitschko exerted his class by repeatedly landing with the jab before throwing a huge right hand then left hook that sent Joshua down for the first time in his career.
Returning to his feet after an eight count, he simply looked out of his depth, uncertain about how to respond and remaining that way until the end of the seventh.
Entering the eighth for the first the time and clearly tired, Joshua again fought with more ambition, but was learning on the job while his experienced challenger remained composed, jabbing and succeeding with another right.
Only in the ninth did he again look the more positive of the two, but with the concern that Klitschko was using his experience to patiently wear him down while pursuing the upset.
The Ukrainian followed that with another big right in the 10th, when the 27-year-old Joshua - like so many of Klitschko's opponents - again looked short of ideas.
A 65th win of a decorated career again looking likely, Joshua suddenly and dramatically changed the course of the fight and his career by securing victory in the way so many heavyweight greats do.
He rocked Klitschko with a huge right uppercut as further punches secured the knockdown, again sent him to the canvas with another hurtful barrage, and - with Klitschko caught on the ropes - forced America's Fields to intervene after two minutes and 25 seconds after refusing to let up.
Should Klitschko never fight again - and as once was likely it seems certain his record of 18 title defences will never surpass Joe Louis' 25 - there is little question he will be remembered as one of the finest ever heavyweights.
His retired older brother Vitali also left a big impression on the division, in which it will be hoped Joshua can achieve the same success enjoyed by the last dominant British heavyweight Lennox Lewis, who retired 14 years ago.
On Thursday at the final press conference before this fight, 1996 Olympic champion Klitschko confidently insisted he had recorded his prediction of its outcome and will auction it off hereafter. If it was more than just a mind game, he will likely be hoping the buyer keeps it to himself.