David Hancko and David Strelec each exploited mistakes in Germany's defence to give Slovakia - who last qualified for the World Cup in 2010 - a surprise lead in Bratislava on Thursday. The visitors couldn't find a way through the Slovakian defence to get back into the game.
It was a blow to coach Julian Nagelsmann and his new-look line-up, including Newcastle's new striker Nick Woltemade in his third Germany game and 21-year-old Nnamdi Collins making his debut at right back.
Nagelsmann was scathing about his team, which he said lacked "emotionality" on the field and the will to win against motivated underdog opposition. He even questioned whether he should pick less skilled but more dedicated players instead.
"Maybe we really do need to rely less on quality and instead on players who just give everything, because that would have led to better results today than if the best players played," he told broadcaster ARD.
Nagelsmann said Germany now need to win all of their remaining five games to avoid the playoffs.
Germany, including West Germany's record during the Cold War, have played at every World Cup since 1954. Until Thursday they had only ever lost three World Cup qualifiers, all at home.
The loss in Slovakia was also only the second time Germany had lost a World Cup qualifier by more than one goal. The other was a 5-1 home loss to England in 2001.
It was Germany's opening game in Group A, which also saw Northern Ireland beat Luxembourg 3-1 on Thursday.
European champions Spain took an early lead with Mikel Oyarzabal's fifth-minute goal and eased to a 3-0 win over Bulgaria in both teams' opening qualifying game. Marc Cucurella and Mikel Merino scored to extend Spain's lead.
Ugurcan Cakir's leaping save in the 11th minute of added time meant Turkey held on to beat Georgia 3-2 in their opening qualifier.
Matty Cash scored to salvage a 1-1 draw for Poland, which ended the Netherlands' perfect start to qualifying.
Lithuania and Malta drew 1-1 in Thursday's other Group G game.
Belgium started slowly against tiny Liechtenstein and only led 1-0 at halftime but turned it into a 6-0 rout, including two goals from Aston Villa's Youri Tielemans and one from Napoli's Kevin de Bruyne.
Wales went top of Group J with a 1-0 win over Kazakhstan, but have played two games more than third-placed Belgium.Â
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