An 85th minute winner from Eljif Elmas ended a 35-game unbeaten run that the four-time World Cup winners had amassed, including victories in their 18 previous qualifiers.
The last time Germany lost at home in a World Cup qualifier was twenty years ago, in a 5-1 win for England in 2001.
Although the home side dominated with 70% possession in the first half, Goran Pandev put the Balkan country into the lead during stoppage time before the break.
In form Manchester City midfielder Ilkay Gundogan converted a spot kick to level the match in the 63rd minute, after former club teammate Leroy Sane had been fouled in the area.
Shortly before Elmas seized the dramatic winner for North Macedonia — sparking jubilant scenes in Duisburg’s Schauinsland-Reisen-Arena — Chelsea striker Timo Werner missed a golden chance to put the Germans in front after a cross from Gundogan.
“We’ve never beaten a team with so many titles. Now, we have to get some rest as what we have accomplished still hasn’t sunk in.”
The loss for Germany was Joachim Loew’s first as a manager in World Cup qualifying, and comes in what will be his last qualifier in charge of the team, before he steps down following this summer’s European Championship.
“Overall, it was disappointing to lose like that at home.”