PSV manager Peter Bosz had to do without star forward Ruben van Bommel, who was deemed too unfit to feature against ADO Den Haag. Youngster Ayoni Santos replaced the recent Oranje debutant for his maiden PSV start, with Dennis Man on the right and Sven Mijnans still the de facto striker, with Ricardo Pepi and Alassane Plea out.
A rather quiet opening phase was broken open by Mijnans, who timed his run perfectly and slotted Guus Til's cut-back neatly into Kilian Niekiema's far corner after 20 minutes.
But disaster struck for PSV in the final 20 minutes of the first half, with Guus Til forced to come off after an unlucky landing and Mijnans going from hero to zero after picking up two yellow cards in the space of five minutes, first for holding a shirt and later for a reckless tackle on the edge of ADO's box.
Playing against 10 men opened up opportunities for promoted ADO, and the The Hague side levelled with PSV just ten minutes into the second half via Juho Kilo, whose long-range effort was deflected into Kovar's bottom corner.
PSV focused on keeping ADO Den Haag at bay but still tried their luck down a man, with Amir Bouhamdi inches away from restoring the reigning champions' lead after hitting the crossbar.
ADO Den Haag were unable to find a seam in PSV's disciplined backline, and PSV found a breakthrough once more in the final ten minutes, but Mikkel Bro Hansen's shot landed in the hands of Niekema.
The closing minutes saw chances on either side, but Sergino Dest's curled effort sailed just over ADO's goal and Evan Rottier had two balls go closely past the past.
But with seconds to go, Czech winger Matej Sin sealed three nigh unlikely points with a tricky header at the far post, which didn't look unsaveable for his compatriot Matej Kovar.
PSV's second loss in three Eredivisie games gives league leaders Feyenoord the chance to take a four-point lead with a win away at Telstar on Saturday evening.
Flashscore Man of the Match: Juho Kilo (ADO Den Haag)