The Monaco-born driver set the standard in his upgraded car with a time of one minute 36.052 seconds, 0.084 faster than Red Bull's Max Verstappen, who has won the previous two races in Singapore and Malaysia and was also triumphant in Austin last year.
Leclerc - whose car has changes to the floor, sidepod and diffuser - won at the circuit outside Austin in 2024.
McLaren's reigning champion Lando Norris was third fastest, 0.245 off the pace, with the Mercedes of George Russell and Antonelli 0.326 and 0.481 slower than Leclerc respectively.
Antonelli, 20, can become the youngest ever Formula 1 champion if he wins Sunday's race and results go his way. Otherwise, the Italian will have to wait until at least Mexico the weekend after.
Ferrari's Lewis Hamilton was sixth on the timesheets ahead of McLaren's Oscar Piastri, Audi's Gabriel Bortoleto and Racing Bulls pair Arvid Lindblad and Liam Lawson.
Lindblad and Bortoleto are both set to take grid penalties for Sunday's race after power unit component changes.
The track has drawn criticism from some drivers for how bumpy it has become.
"Probably the bumpiest track we've had so far this year. It's tricky but I'm sure we'll work around it," Alpine's Pierre Gasly told Sky Sports television.
His Argentine teammate Franco Colapinto will have a 10-place grid drop after a new control electronics unit was fitted.