FC Twente lost a step in the battle for the UEFA Champions League ticket after Ryan Flamingo's powerful header put PSV up one within 15 minutes, giving NEC Nijmegen the edge in a tense fight with Twente and Ajax.
It took Twente mere minutes to respond in clinical fashion - Sondre Orjasaeter's curling effort proved too much for Matej Kovar, who got a hand on the ball but saw it end up in his goal regardless.
A busy opening phase nearly saw PSV retake the lead via Ricardo Pepi, but the American striker was flagged for offside after seemingly scoring the 2-1 in the 21st minute.
Twente were nowhere to be seen after Orjasaeter's goal, as PSV created the bulk of the chances and came close to taking the lead again via Paul Wanner, whose powerful shot in the 30th minute hit Przemyslaw Tyton's crossbar.
After Twente forced a smart save out of Kovar, Belgian youngster Noah Fernandez restored PSV's lead on the cusp of half-time by burying a shot from distance into Tyton's bottom corner.
FC Twente's hopes of finishing third looked all but gone quickly in the second half when Dennis Man fired the ball in past Tyton's near post.
World Cup hopeful Guus Til further dumped Twente in worry with PSV's 100th goal of the season, beating 39-year-old Tyton once again with a low shot.
An 84th-minute penalty sealed FC Twente's fate, with Ricardo Pepi's spot-kick closing the game out with a 5-1 score. Results elsewhere meant that FC Twente finished fourth in the Eredivisie and will enter the UEFA Europa League qualifying rounds next season.