The Dutch striker scored in the 53rd minute to seal the win for his side at the Arena AufSchalke amid rumours that he could be heading back to Real Madrid in the next few days.
Two other former Real players Klaas-Jan Huntelaar and Raul were on the losing side as they disappointed in a generally poor performance from the hosts, who started 2011 with a second defeat of the season to Hamburg after losing 2-1 on the opening day of the season.
Christoph Moritz prevented Schalke from falling behind in the 26th minute as he made a goal line clearance after Manuel Neuer had misjudged a corner and was beaten to the ball by Gojko Kacar.
Moments later, Schalke were claiming a penalty at the other end when Eljero Elia handled inside the area, but the referee waved play on.
An even game was goalless after 45 minutes with both sides unable to stamp their authority on the proceedings.
Elia had the first chance of the second half, but sent his shot wide of the goal.
The northern Germany side then took the lead in the 53rd minute through Van Nistelrooy.
The Dutchman headed in Guy Demel's cross at the far post to beat Neuer from close range and earn his side all three points.
Schalke's reaction was too little too late as Christian Pander sent a free-kick wide from 25 yards before Lukas Schmitz shot into the side-netting when well placed at the far post as the game entered stoppage time.