Yunus Malli struck either side of half-time, sandwiching a Jhon Cordoba goal.
Javier Hernandez pulled one back in the second-half but it couldn't spark a comeback; die Werkself's first game without Roger Schmidt was one to forget.
Mainz went ahead early on and didn't look back. Yunus Malli had almost found a way through to Bernd Leno on two prior occasions, but made it count on the third. Some lovely hold up play by Cordoba saw him find Pablo de Blasis, who fired a fantastic first-time pass into Malli's path. He lifted the ball over the oncoming Leno, giving his side the lead.
Leverkusen responded, specififcally through Hakan Calhanoglu, as they drew two good saves from Loris Karius. But during a period of pressure, Mainz struck again. A hopeful pass forward was headed away by Wendell, but only as far as Cordoba. The powerful striker took the ball out of his feet and struck a powerful shot that went through Leno and into the far corner.
Malli seals the deal
Mainz had further opportunities to extend their lead before and after the break, but it wasn't until just before the hour mark that Malli confirmed the win. Tin Jedvaj handled in the area from the Turk's volley. He stepped up to the spot and confidently converted to heap further misery on the visitors.
Despite being second best for nearly all of the 90 minutes, Leverkusen's consolation goal was something special. A deep free-kick to the back post was met by Admir Mehmedi, who headed on to Hernandez and he applied the finish from close range. Karius was forced into another strong save by Karim Bellarabi late on, but it was a deserved win for the hosts who rise to fifth. Leverkusen drop to sixth.