Two goals apiece for the attacking duo and a tap-in from Stefan de Vrij left Vicente del Bosque's men totally torn apart in the first game of their title defence.
The Netherlands gained a measure of revenge for a FIFA World Cup final loss four years ago by demolishing Spain 5-1 on Friday.
Andres Iniesta scored in extra time to give Spain a 1-0 win and the trophy in South Africa four years ago, and it appeared the same result was on the cards in Salvador when Xabi Alonso powered home a first-half penalty.
But the Netherlands hit back in stunning fashion, with Robin van Persie and Arjen Robben in scintillating form.
Van Persie levelled matters with a fabulous header on the stroke of halftime, before Robben - who fatefully missed a one-on-one with Iker Casillas in the 2010 final - gave Louis van Gaal's side the lead eight minutes after the interval.
Things went from bad to worse for Spain when Stefan de Vrij nodded home a third on 64 minutes, before Van Persie and Robben netted again to complete a remarkable rout in Group B's opening fixture and cast further doubt over Spain's chances of winning a fourth straight major tournament.
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Spain boss Vicente del Bosque forewent the temptation to start with Cesc Fabregas in the false-nine role that was so successful during UEFA Euro 2012, instead choosing Diego Costa as an out-and-out striker.
Costa's impact on the system was evident, too, as Spain opted for a more direct approach than in previous tournaments.
It was the Netherlands which created the first opening, Robben's inch-perfect through ball finding Wesley Sneijder, only for the playmaker - making his 100th international appearance - to shoot straight at Casillas.
Costa then spurned a couple of half-openings as Spain began to find its feet and the Netherlands' defending became increasingly desperate.
It was a last-ditch tackle that led to the opener, De Vrij's sliding challenge bringing down the lively Costa - with Alonso coolly converting from the spot.
Van Gaal's side enjoyed a good spell thereafter, but Spain threatened again on the stroke of halftime as Jasper Cillessen kept out David Silva's cute dink following a stunning Iniesta pass.
That miss would become all the more important soon after, Van Persie looping a superb diving header over Casillas after being picked out by Daley Blind's sumptuous long, diagonal ball.
Picking up where they left off, the Dutch went ahead soon after the break.
Another searching Blind delivery found Robben, who controlled and turned Gerard Pique before slotting home.
Spain suddenly had no answer to Holland's new-found verve, Van Persie rattling the crossbar with a vicious strike.
The woodwork could not save Del Bosque's men soon after, though, as De Vrij atoned for his earlier misstep by heading Sniejder's deep free kick in off the post.
Spain captain Casillas was visibly rattled, and an uncharacteristic sloppy error from him 18 minutes from time enabled Van Persie to notch his second goal of the game.
The Netherlands was not finished there, as Casillas was forced to pick the ball out of the net again as the irresistible Robben took advantage of more lax defending to race clear and round off a scarcely believable result.