Leclerc set the pace of one minute 35.291 seconds in a sunny second practice session at Austin's Circuit of the Americas on Friday (Saturday AEDT) after also lapping fastest in the earlier session with a time of 1:36.052 in his upgraded car on a bumpy track.
Antonelli, the 20-year-old who must win on Sunday to have a first chance of taking the title, was fifth in session one when Red Bull's Max Verstappen was closest to 2024 winner Leclerc.
The Italian, who complained about his seat moving, then improved to second place and ended the day 0.042 off the pace.
Verstappen, winner in Austin last year, is chasing his third successive victory after Singapore and Malaysia.
He ended second practice as the third fastest and 0.189 off Leclerc, with Ferrari's Lewis Hamilton fourth and Mercedes' George Russell fifth.
Russell had a black-and-white warning flag for an incident with Leclerc that led to the Monegasque going off track early in the second session, but stewards decided against any further action.
McLaren's reigning champion Lando Norris was third fastest, 0.245 off the pace, in first practice and then seventh later on and behind Racing Bulls' Liam Lawson.
Norris's teammate, Australia's Oscar Piastri, was just behind the Englishman in eighth place in the second session, after being seventh in the earlier practice.
"I think Lando is definitely a lot quicker than his lap time," McLaren boss Zak Brown told Sky Sports television.
"He didn't get his third sector in. His first two sectors were very strong, so I think we are much quicker than we looked. I think Ferrari's lap time, Mercedes' lap time, there or thereabouts."
Audi's Gabriel Bortoleto, Racing Bulls' Arvid Lindblad and Alpine's Franco Colapinto all collected grid drops for changes to their power units.
Lindblad will drop five places from wherever he qualifies on Saturday, Colapinto 10 places and Bortoleto 20.
Williams looked to be struggling, with Carlos Sainz 20th and Alex Albon 22nd in practice two.
"The car is a mess right now. It's a mess. I have no confidence in the rear," Sainz said over the team radio.
