The absence of the Belgium midfielder, who is expected to join City for a Bundesliga record transfer, did not distract the Wolves as they took the lead when Dutchman Bas Dost volleyed the ball in from Christian Traesch's cross in the 17th minute.
Teenager Leroy Sane squandered a good chance for Schalke from 10 metres before the hosts doubled their advantage when Sead Kolasinac brought down Luiz Gustavo and Ricardo Rodriguez sent keeper Ralf Faehrmann the wrong way with a well-taken penalty in the 59th minute.
Swiss defender Rodriguez then drove over a corner that Timm Klose volleyed in for Wolfsburg's third goal in the 61st minute, with Schalke's back line in disarray.
Wolfsburg, who also left out Inter Milan target Ivan Perisic, now have seven points from three games.
Champions Bayern Munich take on Bayer Leverkusen on Saturday with both teams on six points. Borussia Dortmund, also on six, host Hertha Berlin on Sunday.
(Reporting by Karolos Grohmann; Editing by Tony Jimenez)
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