Chisora caught Scott with a heavy right hook in the sixth round, and the American took to his knees. Scott appeared unhurt from the shot but took his time getting back to his feet and was counted out.
The American was angered at the referee's call as he claimed he'd beaten the count but the decision stood, bringing an end to one of the strangest and most controversial conclusions seen to a top-level fight for several years.
Chisora's win is a shot in the arm for his career after losing four of his last six bouts, and he immediately announced his desire to fight Vitali Klitschko for the world title.
"I knew if I caught him he was going to go down, and I caught him. I want to go back to Germany and fight Vitali again," Chisora said afterwards.
"“It was the most nervous I have been before a fight, because I just couldn’t afford to lose."
The unbeaten Scott was the much better fighter in the opening three rounds, fighting behind his jab and tying up Chisora whenever the Brit got close. The 32-year-old Philadelphia-born boxer used his superior reach to great effect, elegantly moving around the ring opening up on 'Del Boy' when the opportunity presented itself.
In comparison, Chisora looked sluggish in the initial rounds as he followed the American into the corners, trying to get in close in an attempt to break through Scott's guard.
The 6' 5" American was clearly ahead on points before Chisora started to find his feet and connect with some solid combos, and the home town fighter looked to be clawing back the points deficit by the end of the fifth round.
The sixth round was going the way of the American until the Zimbabwean-born, Chiswick-based Brit closed down his opponent, pinned him against the ropes and landed a powerful, if quite messy, right hook.
Scott referred to it as "the equilibrium shot" in the post-fight interview as Chisora's right caught him just behind the ear.
The punch was significant enough to drop the American to his knee before a wry smile appeared on the face of Scott, who seemed unfazed by the shot despite going to the canvas.
The referee's figure loomed over the crouching Scott as the count began. The American looked certain to carry on but took too long, attempting to stand up on the eight count with the fight waved off as he stood straight.
Scott felt certain he had beaten the count, saying: "I'm a professional. Dereck hit me with a good shot. I gave myself an eight-count and was up at nine."