Germany international Leon Goretzka put them ahead after 13 minutes and Guido Burgstaller scored for the second straight game in the 74th to make sure of the three points.
Schalke, who have had a rocky start to the season under coach Domenico Tedesco, had control of the game and allowed only one shot on goal from Mainz the entire first half.
Leaders Borussia Dortmund, two points clear at the top on 19, travel to Eintracht Frankfurt on Saturday, hoping to bounce back from last week's defeat by RB Leipzig and their surprise midweek draw at Cyprus's APOEL Nicosia in the Champions League.
Champions Bayern Munich will be looking to make it two league wins in a row under coach Jupp Heynckes when they take on Hamburg SV.
(Reporting by Karolos Grohmann; editing by Rex Gowar)
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