Van Persie pounced in each half as the Dutch recovered from a controversial Xabi Alonso penalty to inflict a crushing defeat on the reigning kings of world and European football.
Stefan De Vrij got the Netherlands’ other goal as Spain slumped to the heaviest defeat ever inflicted at a World Cup on the reigning champions.
It was Spain’s worst defeat in more than half a century, coming 51 years after a 6-2 defeat to Scotland in 1963. (Match in pics)
Thousands of fans gathered in Madrid to watch the game on giant screens were left stunned into silence by the rout.
The extraordinary Group B drama in the northern Brazilian coastal city of Salvador has potentially turned the World Cup permutations on their head.
If Spain fail to recover the form which saw them win back-to-back European titles either side of their 2010 World Cup triumph, they could conceivably crash out in the first round, or face a daunting clash with Brazil in the last 16.
The walloping eclipsed more refereeing controversies on the second day of competition.
FIFA officials earlier defended Japanese referee Yuichi Nishimura after he awarded Brazil a bitterly contested penalty in their opening game victory over Croatia.
Referees chief Massimo Busacca insisted Nishimura had been justified in awarding the spot-kick after an alleged foul by Dejan Lovren on Brazilian striker Fred.
“He had a very good position,” said Busacca, referring to a photo of the incident which appeared to show Lovren’s hands making contact with Fred.
“When he saw the hands doing something he makes it (the decision).”
But no sooner had referees chief Busacca sprung to Nishimura’s defence then the standard of officiating was again under scrutiny as Mexico took on Cameroon.
Mexico’s Oribe Peralta scored the only goal of a rain-lashed Group A game in Natal, securing a precious three points for Miguel Herrera’s side.
But the main talking point after the game was Colombian referee Wilmar Roldan who chalked off what looked like two valid Mexico goals in the first half.
“The referee has taken two goals off us but we go away with three points and in top spirits,” Mexico coach Miguel Herrera said.
Football chiefs have introduced the use of goal-line technology at this World Cup, anxious to avoid a repeat of the fiasco at the 2010 tournament when England’s Frank Lampard saw a legitimate goal not given in his team’s last 16 match with Germany.
FIFA President Sepp Blatter said earlier this week the use of technology should be taken further, suggesting the introduction of a possible video-replay based challenge system similar to those used in other sports.
However referees chief Busacca said Friday he was unconvinced more technology was the answer.
“When the situation is clear 100 percent of course it (technology) can really help the referee to say ‘Yes, the player scored a goal by his hands’. But these situations are very rare,” Busacca said.
In a separate controversy, the pitch in the Amazon city of Manaus due to host its first World Cup match when England play Italy there on Saturday is not up to the required standard, according to world players union FIFPro.
There are large dry areas on the pitch and some of it has been spray painted green, according to reporters who have been to the stadium.
Neither England nor Italy have officially complained ahead of the much-awaited Group D game on Saturday.
Friday’s other games in Group B sees Chile take on Australia.