'The Takeover' unlocked 'The Matrix' in Las Vegas to become undisputed lightweight champion, out-thinking the two-time Olympic champ.
The fight went the distance with the Honduran-American boxer (16-0, 12 KO) beating two-time Olympic champion Lomachenko handily on all three scorecards.
Lopez takes his record to 16-0 with the Ukrainian icon now 14-2.
Billed as a battle of Lopez's youth and power against Lomachenko's experience, pace and technique, the Brooklyn-born 23-year-old showed there was much more to his game than hard punches.
Hailed before the fight as the best pound-for-pound boxer on the planet, Lomachenko was surprised by the youngster who made a measured and calculated start, throwing uncustomary jabs and cutting off the angles with slick footwork.
A late surge from the favourite was not enough to claw the situation back with Lopez given the fight 116-112, 117-111, and 119-109 as Lomachenko suffered his first defeat since 2014.
"I had to dig deep. I’m thankful, I’m grateful, and each and every day I take that in. I had to dig in there, and it feels good." - Teofimo Lopez
Many expected Lopez to come out swinging thinking that his only real chance was to use his superior power to knock out his Ukranian opponent at 61.2kg (135lbs).
All wrong. Before the bell went Lopez said he knew how to win and laid it out post-fight.
“You just gotta keep pressuring him, putting the gas on him. Stick the jab, don’t give him that opportunity to set up,” he said. “Every time he wanted to throw, I had at least something for him coming back.”
The 23-year-old set the pace in the opening rounds and kept the intensity high, landing a greater percentage of his power punches than the 32-year-old boxer is used to taking.
In his first fight since since August 2019 when he retained his WBA and WBO titles by defeating London 2012 bantamweight gold medallist Luke Campbell, Loma did not find his rhythm until the eighth round which was too late.
Traditionally Lomachenko starts carefully, downloading data on his opponent before working out a way to win with superior technical and tactical skills, but in Las Vegas it was Lopez who unlocked 'The Matrix.'
The underdog's trainer and father, Teofimo Lopez Sr, could be heard in the early rounds saying, "See? I knew we could hurt him."
There was drama and excitement right to the final bell as Lopez went for the knockout, landing a big right followed by a pair of uppercuts.
Lomachenko was in serious trouble when the referee split them after an accidental headbutt opened up a huge gash over Lopez’s right eye.
“I think in the first half of the fight, he got more rounds than I did," he said dejectedly afterwards.
"But in the second half, I took it over, and I was much better. But I want to go home and review the fight," he said through his translator, manager Egis Klimas.
"Right now I can’t comment too much about it, but definitely I don’t agree with the score cards." - Vasyl Lomachenko
Lopez ignored his father's instructions to protect his lead in the closing stages, going for the stoppage.
He said, "I knew (Lomachenko) was coming. I can’t give him that. I don’t know if (the judges have) got him up on the score cards or not. I come to fight, and I come to win.
"I can bang, too. I don’t care, man. I’ll take one to give one. That’s what a true champion does. I find a way to win.”
Although the WBC lightweight belt had been held by Devin Laney, WBC president Mauricio Sulaiman declared during the week that the winner would claim his organisation's belt as well.
The fight was one of the most eagerly anticipated of the year with Lopez, who represented Honduras at Rio 2016, producing a big upset.
Former heavyweight king Mike Tyson, a fellow Brooklyn boxer, led the acclaim for his performance.
Two-time Olympic boxing champion Claressa Shields thought Lomachenko had done enough in the second half of the fight to earn a draw.
And she was surprised at the margin of victory on the scorecards.
So what does it all mean?
This is a tectonic shift, Lopez upset the favourite and reset the world order in lightweight boxing.
Lomachenko didn't agree with the scores on the night, but there was no rematch clause in the contract so there is no obligation for Lopez to meet him again.
The Ukrainian national hero will take stock and discuss what's next with his team which involve dropping down in weight to super-featherweight (59kg/130lbs) or even featherweight (57.2kg/126lbs).
On the other hand, Lopez feels invincible right now.
"Take me to 140 (lbs - light welterweight)," he said, "or I can fight the two-time champion Devin Haney if they want that."
“All it is, man, ‘The Takeover,’ it’s time for the new generation to come up. It’s me taking the lead for everyone.” - Teofimo Lopez