The Stuttgart showdown pits two of the most impressive teams at the tournament against one another, where the victor will earn an equally daunting semi-final date with either Portugal or France.
Julian Nagelsmann's men arrive back on home turf fresh from a comfortable 2-0 last-16 success over Denmark, where they overcame a thunderstorm delay to prevail through Kai Havertz's penalty and a Jamal Musiala effort.
Die Mannschaft's reward is a 19th men's quarter-final in major tournaments - their fifth at the Euros following 14 appearances in the last eight of the World Cup - but defeat would represent an unwanted first.
Should Germany come out on the wrong end of the scoreline on Friday night, they would become the first host nation to be knocked out of the men's European Championships at the quarter-final stage.
On the four previous occasions where the hosts have reached the last eight, all four have seen the home favourites progress, starting with England edging out Spain in a penalty shootout in the 1996 competition.
Spain seeking to emulate 2008 heroes in Stuttgart
Four years later, the Netherlands crushed Yugoslavia 6-1, before Portugal sunk England in the Euro 2004 quarter-finals on penalties, and France ran out 5-2 winners over Iceland in the 2016 edition.
On the other side of the coin, Spain could become the first men's team to knock the Euros hosts out of the tournament in the quarter-finals, and La Roja possess the fonder memories of their most recent Euros encounter.
It has been 16 years since Spain bested Germany in the Euro 2008 final thanks to a Fernando Torres winner, but La Roja have prevailed in just one of their last five meetings, a 6-0 Nations League dismantling in November 2020.
Three of the last four contests between Spain and Germany have ended in a low-key 1-1 draw - including at the 2022 World Cup - and there has already been some fighting talk between the two camps.
A Germany loss would also mark the final match of Toni Kroos's career, and Joselu - his former Real Madrid teammate - has outlined his intention to "retire" the midfielder on Friday evening.
However, it has been 89 years since Germany were last beaten on their own territory by Spain, winning five and drawing three of their subsequent eight battles in front of the home crowd since that inaugural 1935 friendly loss.