PSV struggled in he first half before Danny Koevermans netted a corner from close range to break the deadlock on the stroke of half-time.
Orlando Engelaar doubled the lead early in the second half with a fine header before Nordin Amrabat scored the final goal.
Stein Huysegems and Rihairo Meulens both scored within three minutes in the second half to earn Roda JC Kerkrade a 2-0 win at second division Go Ahead Eagles Deventer, who reached last season's semi-final.
Utrecht and AZ Alkmaar also registered fourth round wins by beating second division opponents. Utrecht beat AGOVV Apeldoorn 2-0 while Alkmaar hit three to sink Eindhoven.
On Tuesday, Twente Enschede beat second division leader Zwolle on penalties.
Ajax Amsterdam will be in action on Thursday at home against Veendam.
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