The McLaren driver put in a flying late lap of one minute 17.600 seconds at the Autodromo Hermanos Rodriguez to top the timesheets by the slimmest of margins, 0.001 faster than Antonelli who is poised to become Italy's first F1 world champion since 1953.
Ferrari's Charles Leclerc, fastest in both Friday sessions, was third quickest and 0.117 off the pace, with McLaren's Oscar Piastri fourth.
Red Bull's four-time champion Max Verstappen, who has a one-place grid drop for Sunday's race, was fifth fastest ahead of Ferrari's seven-time champion Lewis Hamilton.
George Russell, Antonelli's teammate and closest rival, was seventh.
Russell is 123 points behind Antonelli and has to win on Sunday to prevent the Italian from taking the title in Mexico. Antonelli will be champion if he finishes ninth or higher.
Japan's Ryo Hirakawa, replacing Frenchman Esteban Ocon at Haas and set for his F1 debut at the age of 32, was 19th fastest.
Audi's Gabriel Bortoleto and Cadillac's home hero Sergio Perez failed to set any timed laps, with both having changes to their cars' power units ahead of qualifying.