Spain took the lead in the 27th minute with Xabi Alonso converting from the spot after a foul on Diego Costa.
But that was the last of the celebrations for the team known as La Roja — a team which Spain's El Pais newspaper sad was defending not just a title but a style of play.
After Xabi's conversion, it was festival of orange with Van Persie beginning the show with a brilliant diving header just before half time.
Robben then scored in the 52nd minute before Dutch defender De Vrij followed up in minute 64.
Spain goalkeeper Casillas then made a terrible mistake on a dismal night for the team's defence, failing to control a back pass, and allowing Van Persie to score his second.
Robben then completed the humiliation with a fifth goal for Holland in the 80th minute, a goal which also handed him a brace on an evening that may go some way towards easing Holland's painful memories of their World Cup final defeat to Spain four years ago.
The match also saw Spain's goalkeeper Iker Casillas come up short in his bid to break Italian goalkeeper Walter Zenga's long unbeaten World Cup record on Friday.
Had Casillas kept a clean sheet until at least the last four minutes of Spain's Group B opener against the Netherlands in Salvador, he would have overtaken Zenga's 517-minute unbeaten run from Italia 1990.
Casillas had not conceded a World Cup goal since Rodrigo Millar scored in the 47th minute of world champions Spain's final group game 2-1 victory over Chile in South Africa four years ago.
But when Dutch striker Robin van Persie netted in the 44th minute of Friday's clash, to equalise Xabi Alonso's earlier penalty, Casillas's run stopped at 477 minutes, 40 minutes short.
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.
Spain now face a potentially bruising match against a physical Chile side, a game that could decide their fate in a Brazil World Cup that is certainly not going as planned.