As for Stuttgart, despite Christian Gentner's early opener, they now look doomed for the drop - only a favourable set of results would see them maintain top-flight status.
After that, however, Mainz scored three unanswered goals through Yunus Malli, Jhon Cordoba and Karim Onisiwo to seal a superb victory.
Level at the break
Things began brightly for the hosts, after captain fantastic, Gentner, gave them the lead after just six minutes. A full house was soon exploding with noise as Daniel Didavi worked his way inside and set up Philip Heise to shoot at goal. The left-back caught the ball sweetly, but a crucial touch from Gentner deflected it past Loris Karius.
It could have been even better just moments, when Filip Kostic delivered a teasing ball to the back post and picked out Lukas Rupp. The midfielder somehow managed to slam the ball into the ground and over Karius, only to see Niko Bungert make an incredible acrobatic clearance on the line.
From there, Mainz got back into the game and produced their own move of quality to do so. Cordoba did exceptionally well to burst through the midfield and hold the ball long enough for Onisiwo to make a meaningful run. He slid past Kevin Großkreutz and centred for Malli, who made no mistake from close range.
Stuttgart were thankful, in the end, that they weren't behind at the half-time interval after Mainz went close from two corners. The first saw Stefan Bell produced a remarkable save from Mitchell Langerak, while his centre-back partner, Bell, rattled the post with the final action of the half.
Mainz make their chances count
The visitors scored their second goal of the game after some good work down the left hand side, although they had plenty of help after a calamity of Stuttgart errors. Fabian Frei managed to dance has way around several defenders before flicking the ball to the back post and Cordoba, who was completely unmarked, to nod home.
If anyone would come out of the game with any credit, Langerak was that man. The Aussie stopper did brilliantly to deny Malli after the defence parted in front of him, and closed the angle well on Cordoba. At the other end, a hopeful Heise free-kick was all Stuttgart could muster.
Ultimately, they were made to pay for that. After Didavi was dispossessed in controversial fashion by Bell, Mainz moved with pace and verve upfield. Cordoba's stunning game was capped off with a run that burst open the shocked Stuttgart back-line and laid Onisiwo's first Bundesliga goal on a plate; 1-3, game over.
It could have been more for Mainz, but Langerak spared any further misery for the home fans. Mainz will be playing in Europe next year, most likely the Europa League unless there is a massive goal difference swing. Stuttgart, on the other hand, now must win next week to stay up - even then, they have to hope that Eintracht Frankfurt can beat Werder Bremen.