The 19-year-old Italian clocked 01:12.720 around the twisting street circuit, eclipsing Ferrari duo Charles Leclerc and Lewis Hamilton, who had dominated Friday's two practice sessions.
Antonelli finished 18th last season in Monaco but this year arrived in the principality leading the championship by 43 points from British teammate George Russell after winning the last four races.
Leclerc was 0.327 seconds slower than Antonelli's best lap on Saturday, with Hamilton 0.331 back.
The session was interrupted after Haas driver Oliver Bearman lost control at Massenet corner and put his car into the barriers, causing significant damage to his rear wing.
"I just totally lost it on the bump... so sorry," Britain's Bearman said over the team radio.
Reigning world champion and 2025 Monaco winner Lando Norris managed to get some track time after his McLaren suffered an electrical failure in Friday's second session. He was ninth fastest.
McLaren carried out extensive work overnight, breaking the curfew, to replace the wiring harness and battery housing.
A statement from race organisers confirmed that they would face no action as it was the first of their four individual (curfew) exceptions for the 2026 season.