A man of the match performance from Thomas Müller separated Schalke 04 and Bayern Munich at the Veltins Arena, the forward setting up Toni Kroos before scoring himself shortly after the restart.
The game had been a nervy affair in the first half with both sides reluctant to over-commit, yet despite this each side had been guilty of missing chances; Mandzukic with a back post header looked certain to continue his rich vein of form but inexplicably missed from six yards out.
For Schalke it was more about containment, the hosts dealing well with Bayern pressure but looking unadventurous when in possession, though Klaas-Jan Huntelaar did hit the side netting during a promising spell for the Royal Blues going into half-time.
In the end they would pay for their caution, Bayern's two goals in rapid succession proving insurmountable as Schalke stumbled to their first defeat of the season.
As Bayern's perfect start to the season continued Borussia Dortmund slipped up against the unlikeliest of opponents; Hamburger SV ending Dortmund's 31 match unbeaten streak in a shock home win.
An early goal from Heung-Min Son gave Hamburg the best possible start, the South Korean scoring in the second minute.
But with the Red Shorts having conceded six goals in their last three games a one goal lead was always unlikely to be enough.
And so it proved with Ivan Perisic scoring at the beginning of the second half to even things up. From here there looked to be only one winner but again Hamburg took the lead, Ivo Ilicevic being put through on goal by an impressive Rafael Van der Vaart to restore a lead that was extended just four minutes later with Son's fantastic solo effort.
Perisic struck again for Dortmund to make it 3-2 but Hamburg held on for a badly needed win.
Another team who picked up their first home win of the season was 1. FSV Mainz, goals from Andreas Ivanschitz and Adam Szalai in the first 25 minutes proving enough to send Augsburg home empty handed.
The Bavarian side may feel that luck was against them in this game with the home side's first goal coming after just ten minutes from Stefan Langkamp's deflected clearance but the away team failed to respond and never really threatened to get back into the game as Thomas Tuchel's side claimed the points.
VfB Stuttgart fought back from a two goal deficit at SV Werder Bremen in a frantic game that finished with both sides having a player sent off.
Bremen got off to a great start when Kevin de Bruyne, on loan from Champions League winners Chelsea, scored in the 23rd minute with things getting worse still for the Swabians when Zlatko Junozovic doubled the home side's advantage going into the break.
Stuttgart finally got the goal that their good play had deserved in the second half with a goal for Austrian striker Martin Harnik bringing the visitors back into it. Cacau equalised less than ten minutes from time but things were to get more dramatic still.
Goal scorer Harnik was shown a second yellow before Bremen's Assani Lukimya followed him down the tunnel just minutes later in a blood and thunder finale that ended with both sides sharing the spoils.
Elsewhere Eintracht Frankfurt broke a Bundesliga record along with Nuremberg hearts as they won 2-1 at home to make it four consecutive victories in the season, a record number for a newly promoted club.
Things did not get off to the best of starts for coach Armin Veh's side as forward Olivier Occean limped off after just twenty minutes, Erwin Hoffer replacing him.
It was to prove an inspired change with the Austrian international scoring the game's first goal only four minutes later. Nuremberg responded well though and played some neat stuff in the midfield to dominate possession after the goal.
Yet despite the home side's domination Frankfurt always looked the more incisive of the two teams and so it proved as Takashi Innui scored a sublime goal, skinning several Nuremberg defenders before scoring with a classy finish.
It proved to be an important goal with Sebastian Polter's strike for Der Club in the 76th minute in vain as Frankfurt ran out narrow winners.
TSG 1899 Hoffenheim picked up their first points of the season with a 3-1 win over a Hannover 96 side that were unbeaten coming into the game.
The game proved to be a topsy-turvy affair with Hoffenheim scoring all of the goals in a match they bossed. Mathieu Delpierre notched an own goal early on that was to be cancelled out just minutes later with a terrific goal by Fabian Johnson.
Despite looking by far the better side it seemed as though Markus Babbel's team would have to make do with a point before Sejad Salihovic's 82nd minute goal, his first ever in the Bundesliga, and a Daniel Williams effort got Hoffenheim up and running for the season.
At the VW Arena VfL Wolfsburg also scored all the goals in a 1-1 draw with SpVgg Greuther Fürth, an own goal by Emanuel Pogatetz in the 28th minute later atoned for by ex-Bayern striker Ivica Olic in a frustrating day for Wolves fans as Bundesliga new boys Fürth ground out another point.
1-1 was the score too at the BayArena with Borussia Mönchengladbach's goalkeeper Marc-Andre ter Stegen keeping Leverkussen at bay and earning a point for his side as the Foals inconsistent start to the season continued.
An early goal from the visitors by Partick Herrman following a terrific assist from Juan Arango gave Mönchengladbach a platform to build on but Michael Kadlec had other ideas, rifling the ball into the top corner less than ten minutes later.
From here on in there was only one side in it and had it not been for Stegen's magnificent display and Andre Schürrle's profligacy, the forward missing a hatful of chances including a penalty, Gladbach could have been on the end of a real hammering.
All square for fellow newly promoted side Fortuna Düsseldorf who kept their fourth consecutive clean sheet of the season in a 0-0 draw with SC Freiburg in a game characterised by what is rapidly becoming trademark dogged resistance from the home side.