Things seemed to be going the visitors' way early on when Radoslav Zabavnik's challenge on Ciprian Marica earned Stuttgart a 19th-minute penalty.
Germany striker Cacau stepped up to the spot, but Mainz goalkeeper Christian Wetklo made a phenomenal save to keep Stuttgart off the board early.
The saved proved big just seven minutes later as Mainz took the lead when Sami Allagui sneaked behind the Stuttgart defense to turn home a fine ball by Lewis Holtby, making his debut on loan from Schalke.
Mainz continued to be the aggressor after the penalty miss, and they doubled their lead two minutes into the second half when Morten Rasmussen - another debutant on loan from Celtic - climbed through the hair to head in another Holtby cross.
The visitors never looked much like coming back, and Mainz actually had chances to extend the lead further. But Mainz will take a well-earned three points to start the season.
BERLIN (AFP) – VfB Stuttgart suffered a shock defeat on Sunday as Mainz ran out 2-0 winners while Hoffenheim, Hamburg and Bayern Munich all picked up wins on the opening weekend of the Bundesliga season.
Mainz's Tunisia striker Sami Allagui, who was making his debut, opened the scoring in the 26th-minute when he planted his shot in the left corner to leave Stuttgart stunned.
Fellow debutant and striker Morten Rasmussen of Denmark then scored the second just two minutes after the half-time break as the home side took the three points.
On Saturday, Hoffenheim got their season off to a flying start when they destroyed Werder Bremen 4-1 to set the early pace.
Fresh from their 3-1 win over Sampdoria on Thursday in the Champions League qualifier, Bremen were humbled as the home side blitzed their hosts in the first 45 minutes.
Bremen took the lead when captain Torsten Frings slotted home an early penalty after a Hoffenheim handball, but it was then all downhill for Werder.
Hoffenheim drew level when Senegal striker Demba Ba netted in the 20th minute, but things got surreal when Hoffenheim netted three goals in six minutes.
The rout started when teenager Peniel Mlapa slotted coolly past Bremen's Germany goalkeeper Tim Wiese on 37 minutes.
Striker Vedad Ibisevic then made it 3-1 when Frings was robbed of possesion by Brazilian midfielder Luiz Gustavo, sprinted downfield and put in a superb pass for his Bosnian team-mate to convert on 41 minutes.
Bremen's misery was compounded just two minutes later when Sejad Salihovic curled in a free-kick which left the Werder goalkeeper stranded as it finished 4-1 at the break and stayed that way.
A late goal by ex-Manchester United striker Ruud van Nistelrooy gave Hamburg three points and sealed a 2-1 win over ten-man Schalke 04 on Saturday night after Royal Blues defender Benedikt Hoewedes was sent off after an hour.
Dutch striker van Nistelrooy scored either side of half-time, including a late winner after Schalke's Jefferson Farfan had equalised with a dream flick of the foot on 80 minutes.
Earlier, Bundesliga history was made in Cologne as Lebanon defender Youssef Mohamad earned the fastest ever red card when he was sent off just 92 seconds into the new season in the 3-1 defeat against newly-promoted Kaiserslautern.
After Austrian striker Erwin Hoffer got around the back of the Cologne defence, Mohamad was the last defender and when he brought down Hoffer, referee Doctor Felix Brych showed him a straight red card.
In the other results, Moenchengladbach drew 1-1 at home to Nuremberg as Cameroon striker Mohamadou Idrissou equalised for the hosts.
Hanover beat Frankfurt 2-1 while newly-promoted St Pauli scored three goals in the last eight minutes to seal a 3-1 win at Freiburg.
On Friday, ex-England manager Steve McClaren and his Wolfsburg side were denied a point as Bayern Munich's Bastian Schweinsteiger latched on to Franck Ribery's cross to seal a 2-1 win with seconds remaining.
Bayern made the perfect start as Germany's Thomas Mueller -- the top-scorer at last month's World Cup -- scored the opening goal after just nine minutes, only for Edin Dzeko to equalise after the break, before Schweini's winner.