Van Persie opened the scoring after 17 minutes and then doubled the hosts' lead just before the half-time interval before Javier Hernandez, who will play for Manchester United next season, pulled one back for the visitors.
Stijn Schaars and Demy De Zeeuw were handed chances to impress in the Dutch midfield, with Khalid Boulahrouz starting in defence as coach Bert van Marwijk prepares to confirm his 23-man squad for South Africa on Thursday.
Mexico, who faced a quick turnaround after losing 3-1 to England on Monday, gave starts to the likes of Hernandez, veteran Cuauhtemoc Blanco and goalkeeper Francisco Ochoa, with defenders Rafael Marquez and Carlos Salcido and striker Guillermo Franco, who is to be released by West Ham, among those to make way.
De Zeeuw had an early attempt on goal for Oranje before Van Persie and Dirk Kuyt both forced saves from Ochoa during a busy opening for the Mexican keeper.
And the early pressure paid off as Van Persie opened the scoring. Rafael Van der Vaart did well to find space on the left of the box and his ball across goal left Van Persie with the easy task of turning the ball home.
Mexico finally began to settle after their poor start, with Gerardo Torrado and Andres Guardado proving lively as Javier Aguirre's side began to look a more threatening proposition.
But they were two goals down after 41 minutes thanks to an excellent Van Persie finish. Ibrahim Afellay was the provider on this occasion, the PSV midfielder's cross allowing Van Persie to meet the ball on the volley and beat a helpless Ochoa.
Both sides made changes at the break and Mexico continued to improve, substitute Pablo Barrera forcing a sharp save from Maarten Stekelenburg with an angled drive.
But the flow of the game was affected as both managers made further changes at regular intervals, although Hernandez took advantage of one of the few clear-cut chances in the second stanza to head home a Jorge Torres cross in the 74th minute.
Stekelenburg did well to keep out Giovani Dos Santos' piledriver, and the Tottenham midfielder then fired wide when well placed a matter of minutes later.
Afellay was narrowly off target with a long-range strike in the dying seconds as the match petered out.