The 20-year-old Italian turned the tables on Ferrari as the Scuderia, who had led the way for all three practice sessions, again fell flat when it came to the crunch in Austin on Sunday AEST.
Antonelli pipped Max Verstappen - winner of the last two races - to first spot on the grid by 0.179 seconds with Isack Hadjar third in the second Red Bull.
Australia's Oscar Piastri and his McLaren teammate Lando Norris managed seventh and eighth respectively.
For Antonelli to claim the crown in the Lone Star State is a tall order; he would need to win the race and hope that teammate George Russell finishes lower than ninth and Lewis Hamilton lower than fifth.
But he did the first part of his job in supreme fashion, delivering a stellar lap to blow away his rivals and underline why he is the champion-in-waiting.
Russell struggled and will line up sixth, while Charles Leclerc and Hamilton managed only fourth and fifth as Ferrari's pace disappeared when it mattered.
Sunday (Monday AEST) represents Antonelli's first shot at clinching the crown but, with a 102-point lead and only 150 left up for grabs ahead of this weekend's tussle at the Circuit of the Americas, it appears merely a matter of when the Italian becomes champion.
"I just need to keep doing my job. I feel I can enjoy it a bit more because I am in a good position," Antonelli said.
"I have a great group of people around me and a lot of friends with me. We play cards together in the evenings and that helps you to stay relaxed."
Ferrari have not been on pole since Leclerc in Hungary in 2025, while Hamilton's wait for top spot in qualifying extends to that same race two years earlier - 1190 days ago.
Hamilton is a five-time winner around the Circuit of the Americas and an upgraded Ferrari appeared to have put him in the mix to end his long wait for a pole position.
Ferrari president John Elkann was watching on from the garage, with pressure on the team to finally deliver in qualifying after a difficult run of races and increased speculation over the future of boss Fred Vasseur.
But Hamilton, 41, whose sole Ferrari win came in Barcelona in June, and Leclerc were again unable to pull it out of the bag.
Both Williams were among the stragglers knocked out in Q1 as their miserable season continued, with Alex Albon fuming "what a s**tshow".
Norris topped the opening run but McLaren chief executive Zak Brown told Sky Sports that Ferrari were "in a league of their own".
Leclerc hit back to lead the way ahead of the final session but Mercedes duo Antonelli and Russell had also come to the fore to suggest the battle for pole would be a tight one.
Antonelli soared to the top of the charts after the first run in Q3 and the Italian's challengers fell by the wayside.
Leclerc lamented Ferrari's Q3 struggles, saying: "We lost one or two degrees of track temp and, for us, it was night and day different and already from the out lap I felt I was having lots of difficulties.
"It's a shame that it happened in Q3 because I strongly believe that we had the pace to be fighting in front but unfortunately not today again."
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