Lomachenko, 31, regarded as one of the best pound-for-pound boxers, was made to work hard for the thrilling win.
Campbell, also 31, was aiming to become a world champion for the first time but was floored in the 11th as the Ukrainian’s class proved decisive.
Lomachenko got the verdict 119-108, 119-108, 118-108 at London’s O2 Arena.
Campbell, an Olympic gold medallist in 2012, suffered the third loss of his 23-professional fight career but deserves huge praise when he fought back to produce a brave performance to hear the final bell.
“He is so good, he adapts to any plans,” said Campbell. “Tonight was not the jackpot but my time will come.”
The Hull man was in trouble at the end of the fifth when he was caught by a crushing left hook and then a barrage of body and head shots, but was saved by the bell.
Campbell took more punishment in the sixth, but had success of his own later in that round and the next in a captivating contest.
He was floored in the 11th after a barrage of body shots and then a jab sent Campbell down. But he got up, although two of the three judges did not give him a round, only a share of one.
Lomachenko lives up to the hype
A sold-out crowd at the O2 Arena witnessed another fantastic, dominant performance from Lomachenko, a three-weight world champion.
This latest victory means he now holds three of the main four belts in the lightweight division – Ghana’s Richard Commey, the IBF champion, the only one standing in his way from being an undisputed champion.
Lomachenko has also held world titles at featherweight and super-featherweight after an incredible amateur career that saw him win 396 out of 397 bouts and also win Olympic gold medals in Beijing in 2008 and then again in London four years later.
Now, less than first miles from that second gold medal and in his first professional fight in Europe, Lomachenko dazzled from the off.
Before the fight, promoter Eddie Hearn said it was an “honour” to get the Ukrainian to fight in the UK – and he didn’t disappoint.
The right jab proved a constant menace and the left was dangerous, twice rocking Campbell’s head back as early as the third round.
He also provided some brutal body shots, leaving Campbell wincing in pain in the fourth.
Campbell leaves with his head held high, but not the belts
In the build-up to this fight, legendary promoter Bob Arum said Lomachenko was the greatest technical fighter in Boxing since Muhammad Ali and afterwards also compared him to other greats including Marvin Hagler, Sugar Ray Leonard, Floyd Mayweather, Oscar de la Hoya and Manny Pacquiao.
Therefore to go the distance shows what a gutsy effort it was from Campbell.
This was his second world title shot after he lost on a controversial split decision against Jorge Linares in America in September 2017.
On that occasion, Campbell, whose father died two weeks before the fight, was knocked down in the second but fought back, with him later insisting he won the fight by a two-round margin.
But against Lomachenko it never looked likely that Campbell, a 10-1 underdog, would get the victory, as the Ukrainian was too good, despite the Briton being two inches taller and having a five-inch reach advantage, with Lomachenko’s excellent and powerful work to the body repeatedly causing Campbell problems.
Lomachenko was fighting a British opponent for only the second time, after knocking out former world champion Anthony Crolla in the fourth round in America earlier this year.
Campbell managed to go the distance, but a shock win was not to happen.
Former world champion Carl Frampton: “I never expected that. It was down to Luke Campbell who showed such skill alongside grit and determination. Even though he lost his stock has probably risen. He is probably in the top five pound-for-pound fighters in Britain now.”
BBC Radio 5 Live Boxing expert Steve Bunce: “We came for sorcery and were given a display of old-fashioned grit, determination and heart and desire. Such bravery, such guts. The points mean nothing. Luke Campbell made the magician look normal.”