A goal in each half from Sofiane Diop and Guillermo Maripan allowed Monaco to leave Paris with the points, stretching their unbeaten run to 11 games and allowing them to move to within two points of their opponents in third place.
While Monaco remain in contention for a return to the Champions League, PSG find themselves a point behind Lyon in second and four points adrift of Lille, who reclaimed top spot earlier on Sunday with a 4-1 win at Lorient.
It was a disappointing night for PSG as they failed to pick up where they left off in midweek, when they destroyed Barcelona in the first leg of their Champions League last-16 tie, Mbappe scoring a hat-trick in a 4-1 win.
While Mauricio Pochettino's side look certain to qualify for the quarter-finals in Europe, there is a genuine chance that PSG will miss out on the Ligue 1 title for the first time since Mbappe's Monaco pipped them in 2017.
Almost exactly five years to the day after he scored his first Ligue 1 goal as a 17-year-old for the principality side, Mbappe was kept quiet by the Monaco defence, while Neymar watched from the stands as he continues to recover from injury.
Monaco had already beaten the Parisians at home in November and they went in front here in the sixth minute when Ruben Aguilar knocked down Kevin Volland's cross for Diop to head in.
The home side failed to muster a shot on target in the first half and they continued to lack inspiration after the break, as Monaco doubled their lead in the 51st minute.
Chilean defender Maripan dispossessed Ander Herrera inside the box and then coolly slotted low into the corner for what was already his fifth goal in 2021.
Mbappe had scored seven times in seven previous games against his old club since moving to PSG in 2017, but he could not add to that tally as Monaco became the first team to beat PSG twice in the same Ligue 1 season since Nancy in 2011/12.
They are the third team to beat PSG at the Parc des Princes in Ligue 1 this season, following in the footsteps of Marseille and Lyon.
Seven straight away wins
Earlier, a superb second-half free-kick from French international Jonathan Ikone helped Lille ease to victory at Lorient.
Lyon had gone provisionally to the summit on goal difference with a 3-2 victory at Brest on Friday, piling pressure on a Lille side who were beaten at home by Ajax in the Europa League in midweek.
However Lille kept up their momentum in the league to make it a club record seven straight away wins in the top flight, with Jose Fonte and Domagoj Bradaric also scoring after Andreaw Gravillon's own goal had put them ahead in Brittany.
Gravillon deflected Jonathan David's shot into his own net midway through the first half, only for Jerome Hergault to equalise shortly after.
However, veteran centre-back Fonte restored Lille's advantage with a low drive from outside the area in the 38th minute and the four-times capped Ikone curled in a free-kick just before the hour mark.
Lorient had gone unbeaten through their previous five outings, notably beating PSG and holding Monaco, to boost their hopes of escaping the drop.
However, Bradaric wrapped up a big win for Lille in stoppage time, plunging Lorient back into the bottom three on goal difference behind Nantes.