The home team recorded its first win of the season as it proved too strong for last year's runner-up in both side's Bundesliga opener.
Leverkusen started the match as favorites, but Mainz grabbed the lead after 32 minutes of play. Fabian Giefer failed to clear the ball and passed it straight into the path of Sami Allagui, who had no trouble finding the net.
The away side wasn't too impressed and came close to leveling the score on a number of occasions, but Mainz goalkeeper Heinz Muller proved to be too much of an obstacle.
The hosts decided the game late in the second half when Omer Toprak was unable to clear a cross from Marco Caligiuri and beat his own goalkeeper.
Mainz has an away match against Freiburg next week, while Leverkusen hosts Werder Bremen on matchday two.