It was the first career defeat for young prodigy Lopez, 24, who couldn't resist the relentless blows from Kambosos, 28.
The new unified champion comes out on a split decision, with the judges handing in 115-111 and 115-112 for the winner, and 114-113 for Lopez.
The boxers offered a fierce fight, both finishing covered in blood and bruises, but outsider Kambosos proved more energetic.
"Ferocious", who fought for the third time in the United States, showed that he was talented, but also knew how to take punches.
Kambosos surprised his opponent at the start with a knockdown on the first round, before falling to the ground himself on the tenth round.
“I didn't have any pain,” Kambosos said.
"I said to my camp: + Let's go all the way. I'm going to punish this kid +".
Kambosos, who remains undefeated in his career (20 victories, including 10 by KO), inflicts a painful defeat on Teofimo Lopez, who himself had created the surprise in 2020 by winning the three belts after his victory against Vasyl Lomachenko.
Lopez interrupted Kambosos' post-game interview to say he was robbed and lost only 2 out of 12 times, triggering boos from the Hulu Theater.
"You're delusional," Kambosos replied.
Australia's George Kambosos Jr during his fight against American Teofimo Lopez in the lightweight category at the Hulu Theater in Madison Square Garden on November 27, 2021, in New York City.
AL BELLO GETTY IMAGES NORTH AMERICA / AFP
“I won tonight,” whispered Lopez.
"The referee didn't put my hand up. I'm not a sore loser. I came here and did what I had to do. I won 10 out of 12 times."
© 2021 AFP