It was revenge for the Dutch who lost 1-0 to Spain in the World Cup final in Johannesburg four years ago.
The last time the reigning champions lost their opening match, France were humbled by Senegal in 2002, but never before had a title-holder been so comprehensively thrashed.
Manchester United forward Van Persie scored twice, including a brilliant lobbed, headed opener, set up another and cracked a stunning strike against the bar in a man-of-the-match performance from the Dutch captain.
Robben went some way to making up for spurning two glorious chances in the final in South Africa by punishing Spain with his speed and scoring a brace of his own.
Stefan de Vrij was another to get his name on the scoresheet after Xabi Alonso had opened the scoring for Spain, who suffered their worst defeat in more than half a century, with a highly contentious penalty after Diego Costa had slumped to the ground in the box despite no contact appearing to be made by De Vrij.