The Manchester United star turned home Wesley Sneijder's pass for the only goal of the game in a competitive World Cup warm-up with the Black Stars
Having missed the 1-1 draw with Ecuador a fortnight ago, big-hitters Arjen Robben, Wesley Sneijder and Nigel de Jong were among five added to the starting XI.
But it was captain Van Persie – scorer of the equaliser against Ecuador – who made the early breakthrough, tapping home from six yards after being teed up by Sneijder.
Robben squandered numerous opportunities to extend the lead, most notably scooping over the crossbar from close range, but the home side's lead never looked in any danger as Ghana battled well but failed to find a shot on target until the dying minutes.
The Netherlands face one more friendly against Wales on Wednesday before departing for the World Cup in Brazil, while Ghana, who saw Jerry Akaminko taken off on a stretcher in stoppage time, are scheduled to meet South Korea next weekend.
After Van Persie had put the Netherlands in front amid some questionable defending from the visitors, it should have been 2-0 seven minutes later, but Robben chipped over from the edge of the six-yard box after good work by Daley Blind down the left.
The frustration of that miss may have been a factor as Robben lost his temper with Rashid Sumaila after a particularly reckless challenge by the defender, before Blind was caught by Michael Essien's elbow - the term 'friendly' apparently lost on the Ghanaians.
Robben had another chance to open his account midway through the half, but goalkeeper Adam Kwarasey made himself big to deny the attacker, and the Norway-based stopper got down well to deny the Bayern Munich man once again on the stroke of half-time.
The 30-year-old looked like a man on a mission, and his free kick whistled just over the crossbar four minutes into the second period, while opponents Ghana offered little going forward.
Ron Vlaar could not direct his headed effort goalwards from a corner 15 minutes from time, before Robben again drew a save from Kwarasey with a drilled strike from a tight angle.
While the Netherlands will be disappointed not to have built on their early lead, they will no doubt be relieved to emerge from the fixture with a clean bill of health.
Ghana's Akaminko was the only major injury concern of the match after appearing to fall awkwardly on his ankle late on, and the visitors will need to work on their attacking threat if they have designs on qualifying from a tough group in Brazil, as they line up alongside Germany, Portugal and the United States.