Needing only a point to secure a place at next year's Nations League Finals, Germany were embarrassed in Seville as La Roja triumphed through a Ferran Torres hat-trick and goals from Alvaro Morata, Rodri and Mikel Oyarzabal.
It was the 2014 World Cup-winners' heaviest defeat since they lost to Austria in a friendly in 1931 by the same scoreline, as Manuel Neuer, who set a new record for a German goalkeeper by winning his 96th cap, conceded six goals in a competitive game for the first time in his career.
The manner of the defeat, described by Low as "awful", was particularly concerning. Germany failed to muster a shot on target, had just 30 percent of the possession, and Toni Kroos (43) was the only player from the visitors to have more successful passes than Spain goalkeeper Unai Simon (41).
It also cast a poor reflection on Low's decision last year to tell Germany stalwarts Jerome Boateng, Mats Hummels and Thomas Muller they had no future with the national team, as the 60-year-old put his faith in younger players.
Fritz Keller, the president of the German Football Federation (DFB), admits there was always likely to be some difficult moments as Germany went through a transition period before Euro 2020.
However, he remains confident Low can turn things around and create a team capable of challenging next year, as well as at the 2022 World Cup and the Euros on home soil in four years' time.
"We had a black evening in Seville, which hurt us," Keller said in a statement. "The viewers at home, me, the coach, the players.
"I was in the dressing room after the final whistle and I felt everyone's extreme disappointment. But also the will to correct this feeling.
"Our young team can grow from the severe setback if this game, in which not only heart and passion were missing, is analyzed carefully and the necessary conclusions are drawn. They have the potential.
"We made a conscious decision to bring about the change with many new and young players with perspective. As was seen yesterday, this path can be the more rocky one and also lead to painful defeats.
"But even if we all wished to get out of this difficult and, up until then, successful year of international matches, our challenge is still to form a strong team for the next three major tournaments: the European Championship next year, the 2022 World Cup and the European Championship on home soil in 2024."