Junior Diaz's first goal in a Mainz shirt and an Adam Szalai effort gave Mainz a two-goal lead before the interval.
Wolfsburg were unable to recover in the second half, wasting chance after chance as their curse at home, where they have not won all season continued.
Felix Magath's side started brightly with the technically-gifted Vieirinha causing problems to the Mainz rearguard.
He had the first chance of the game in the 20th minute, but Christian Wetklo punched his shot away.
Andreas Ivanschitz cleared a goalbound header from Emanuel Pogatetz before it was able to cross the line in the 26th minute, and he then provided the cross for Mainz's opening goal a minute later.
Junior Diaz beat Naldo in the air and sent a looping header over Diego Benaglio, who was caught off his line.
Szalai made it two 10 minutes later when he volleyed in another cross from Ivanschitz to stun the home fans, who were still silent after the Mainz opener.
Wolfsburg continued to attack with Vieirinha sending a shot wide of the target and Pogatetz heading over from close range.
Ivica Olic squandered the best chance of the half midway through with a free header from close range, a miss which epitomised the Wolves' problems.
The desire was clearly there, but the finish was not. Olic again only found the outside netting as the home side kept up their assault on the Mainz goal.
It was an assault which went unrewarded as the toothless Wolves succumbed once again to defeat at home, despite creating chances to win several games.