The welterweight star was going into the bout off the back of a devastating knockout defeat of his own to lightweight star Tony Ferguson last October.
But he showed no signs of letting that defeat get to him at the Bridgestone Arena, as he leapt off one standing foot and unleashed a right hand on Thompson.
With just five seconds left in the second round, Pettis was tagged by ‘Wonderboy’ against the cage, before backing off to land a clean shot.
Thompson was knocked out immediately, and Pettis had to be pushed away as referee Herb Dean stopped the fight, as Pettis wiped away blood from his face in celebration.
It was the first time the 36-year-old had ever been knocked out in his nine-year MMA career.
Fellow MMA stars and fans took to Twitter immediately to congratulate the 32-year-old, who was fighting at welterweight for the first time in his career.
Dillon Danis, Conor McGregor’s jiu-jitsu partner, couldn’t hold back his excitement.
He posted: “Wow that was unbelievable!!! Happy for Pettis!”
Aijamain Sterling, UFC bantamweight, wrote: “I can’t believe that just happened.
“I know Pettis is beast in the stand up department, but I felt Wonderboy’s size and striking would win it. This fight game is crazy.”
One fan wrote: “Anthony Pettis just pulled off one of the greatest comeback wins in UFC history. The first fighter to knock Wonderboy out. This is history”
Former UFC lightweight champion Rafael dos Anjoy immediately called out Pettis for a welterweight fight, but insisted he needs to deal with Kevin Lee first.
“I’ll take care of Lee first then I’ll see you Pettis. Great win btw.”
Former UFC women’s featherweight champion Cris Cyborg posted: “Showtime is back and it’s not in LA!”
Kelvin Gastelum, UFC middleweight champion, tweeted: “Woooooowww that’s the beauty of the sport!! You NEVER know what’s going to HAPPEN! What a crazy fight and KO”