The United striker was consigned to his sick bed and missed training on Tuesday ahead of the Stade de France encounter, with Holland unlikely to take any risks with their captain if he is not fully fit.
Although Michel Vorm and Rafael van der Vaart are also unwell, van Gaal insisted his doctor has confirmed it is not due to a flu bug because the players have different symptoms. Arjen Robben has trained but is carrying a knock and is another who might not start.
"Van Persie and Robben will play anyway at the World Cup," stated van Gaal. "Now I could test other players." However, both stars have not been definitely ruled out with a decision being taken closer to kick-off.
Patrice Evra is a likely starter at left-back for France in the prestigious international in Paris, which starts at 20:00 GMT.