Jens Keller saw his reign as caretaker coach get off to the worst possible start, since taking over from Huub Stevens on Sunday, as an 83rd minute winner from Nicolai Muller proved the difference.
Schalke, who topped their group in the Champions League, went behind on the half-hour mark when Marco Caligiuri opened the scoring, but they levelled the match with 15 minutes to go thanks to Dutch international Klaas-Jan Huntelaar.
Muller then added insult to injury for Schalke with his late winner leaving the hosts with just the Champions League to play for as thanks to a run of just two points from their last 18 in the Bundesliga they are 17 points adrift of leaders Bayern Munich.
Bayern had no such problems winning 2-0 away at Augsburg on Tuesday evening, despite playing for almost the whole of the second-half with 10 men after Franck Ribery was sent off, and avenging a defeat there earlier in the season in the league.
German international striker Mario Gomez' superb form since returning from an ankle operation continued as he scored the opener with his fourth goal in six games.
The runaway Bundesliga leaders doubled their lead five minutes from time as Swiss star Xherdan Shaqiri fired home after being set up by Thomas Müller.
It should have been 3-0 but Ukrainian veteran Anatoly Timoschuk's 30 metres piledriver which crossed the line after hitting the bar was not seen by the referee.
Elsewhere Third Division side Offenbach claimed a top level scalp with a 2-0 home win over Bundesliga side Fortuna Düsseldorf.
The quarter-final line-up will be completed on Wednesday with the highlight of the four games, holders Borussia Dortmund at home to Hannover.