Tony Bellew came up short in his bid to topple undisputed cruiserweight champion Usyk, who claimed a stunning eighth-round knockout win in front of a raucous Manchester Arena.
The Liverpudlian was attempting to become the first Briton to hold all four major world titles - plus the prestigious Ring Magazine belt - in a weight class simultaneously in his final professional bout.
He made a courageous start but was denied the fairytale finish to his career as his unbeaten Ukrainian foe demonstrated why he is rated among one of the finest fighters on the planet.
Usyk gradually started to establish his dominance and closed the show emphatically, flooring his rival with a devastating one-two, prompting referee Terry O'Connor to wave off the count after two minutes of the eighth round.
Usyk therefore retained his WBC, WBA, IBF and WBO titles at 200lbs.
Bellew was gracious in defeat. He said on Sky Sports Box Office: "I tried my best and gave it everything. Usyk is a great, great champion. He beat me fair and square, I have no excuses.
"Oleksandr is the greatest man I have ever shared a ring with. Only the very best and very greatest will find a way to beat him."
Bellew admitted he had just not been able to meet the standard of the Ukrainian.
"You come up against great people in life and sometimes you have to accept it," the British boxer said on Sky Sports Box Office.
"I can't remember what round that was, I don't even remember half of the fight. He's an exceptional champion. Anyone who faces him is in trouble. Only the very best and very biggest will beat him.
"I chose to do this one more time. I now know why he is so great."
Bellew will now retire and sent a warning to anyone thinking of taking on the Ukrainian next.
Speaking to BBC Radio 5 Live, the British fighter said: "He is big and he overpowers you. I tried my best and he is probably the best cruiserweight that ever lived. He is better than what it says on the box.
"Heavyweights stay away, he takes a great shot and I don't even know if I hurt him.
"It is heartbreaking because I gave it everything I had."
Bellew added: "I have been doing this for 20 years and it is over."