In what proved to be a brutal fight that saw both combatants dropped at various stages, it was the Australian who would come out on top to claim the WBA, IBF, and WBO and Ring Magazine lightweight world title belts from Lopez Jr.
The gathered crowd could smell an upset on the cards when, while defending a flurry of wide-arking rights, Kambosos landed a monster counter attack to drop Lopez Jr in the first round.
Lopez was not hurt by the blow, but it sent a very clear message that Kambosos wasn't there to simply take part.
Lopez would then settle as he got into his work, even switching to southpaw at one point in the middle rounds before switching back to his orthodox stance.
Both fighters had to deal with substantial cuts above their eyes, forcing a late stoppage for doctor's checks, as blood streamed down their faces in one of the most heated battles of 2021.
Kambosos stuck to his game plan incredibly well though, despite the fact that he was appearing to tire as the well of adrenaline from his early shot began to run dry.
And, in the 10th round, it looked as though Lopez's power might just bail him out as he sent Kambosos sprawling to the canvas.
Lopez was unable to take advantage, however, and, despite notable exhaustion, a final stages second-wind for Kambosos just about got him over the line to the final bell.
Ultimately, it was Kambosos who would be crowned the new champ, by scores of 115-111 from Frank Lombardi and 115-112 from Glenn Feldman, over 114-113 from judge Don Trella.
It was undoubtedly one of the biggest shocks in a long time, with the boxing world erupting online following the news that 'Teo' had been beaten.
Having predicted that the fight would end in a first-round KO, it proved to be a rather more jarring event for Lopez Jr.