Messi, who started after a club-imposed suspension for missing training last month, was booed by the fans before and during a one-sided encounter that took PSG to 81 points with three games left, thanks to goals by Fabian Ruiz, Achraf Hakimi, a double by Kylian Mbappe and Mohamed Youssouf's own goal.
Christophe Galtier's side lead second-placed RC Lens, who beat Stade de Reims on Friday 2-1 despite being down to 10 men, by six points.
Third-placed Olympique de Marseille, who host bottom side Angers on Sunday, are five points behind Lens.
Ajaccio are 18th on 23 points, 11 points from 16th-placed AJ Auxerre.
The last four clubs in the 20-team Ligue 1 will go down at the end of the season.
Both teams finished with 10 men after Hakimi and Ajaccio's Thomas Mangani were sent off late.
At the Parc des Princes, the crowd jeered when Messi's name was announced in the line-up and the Argentinian was booed when he first touched the ball.
Messi returned to training on Monday after being suspended for making an unauthorised trip to Saudi Arabia and missing a training session as a result.
French media reported that Messi had been suspended for two weeks after making the trip when he was supposed to train with the squad the day after the Ligue 1 leaders' 3-1 defeat to Lorient last month.
Messi apologised to PSG and his teammates last Friday and was left out of the squad for their 3-1 win at second-bottom Troyes two days later.
He was below par on Saturday as PSG bulldozed past Ajaccio.
Ruiz opened the scoring in the 22nd minute with a whipped shot, 10 minutes before Hakimi doubled the tally by poking home the ball from Mbappe's deflected shot.
Mbappe made it 3-0 two minutes into the second half with a shot from a cross and added another goal in more spectacular fashion with a volley from the edge of the box in the 54th.
Youssouf then deflected a Marquinhos cross into his own goal in the 73rd minute, before Hakimi and Mangani were both shown a straight red card for losing their tempers with brutal challenges.