Eric Maxim Choupo-Moting and Nicolai Muller scored as Thomas Tuchel's men made it three wins out of three to join Bayern Munich, Borussia Dortmund and Bayer Leverkusen at the top of the table.
To make matters worse for Wolfsburg, they had new signing Luiz Gustavo sent off as they lost their second game of the season.
Mainz appeared happy to sit back and let Wolfsburg tire themselves out in the first half, rarely touching the ball but at the same time keeping their opponents at a safe distance from their goal.
On the break, Mainz had the first big chance of the game, but Shinji Okazaki lost his nerve with only Diego Benaglio to beat and sent in a tame shot.
A goal-line clearance from Nikolce Noveski prevented Vieirinha from giving Wolfsburg the lead in the 28th minute before Diego missed the target for the guests.
Mainz changed their tactics in the second half and started to attack more often, although it was Ja-Cheol Koo who went close to opening the scoring early on with Heinz Muller making a fine one-handed save.
Mainz took the lead after an hour's play when Choupo-Moting converted from a corner.
The Wolves were reduced to 10 men when Gustavo picked up a second yellow card for a foul on Muller, who then netted Mainz's second and his fourth of the season.
He had no problem beating Benaglio after being put through by Johannes Geis and Mainz held on for their third consecutive win of the season.