The two sides last met in the competition opener in September and played out a 1-1 draw. But the stakes are much higher in Tuesday's game, and we expect a conclusive result from what promises to be an enthralling encounter.
Despite a long injury list, both La Furia Roja and Die Mannschaft have a lot of talented players in their ranks at almost every position, and we will be able to witness some interesting player battles on the pitch.
On that note, here we take a look at the five key battles that might determine the outcome of the game between these two former World Cup winners.
#5 Mikel Oyarzabal vs Matthias Ginter
In the absence of Ansu Fati, it is very likely that Spain coach Luis Enrique will opt for a 4-2-3-1 formation, in which Mikel Oyarzabal has started as an attacking midfielder on the left. His position will likely pit him against Borussia Mönchengladbach defender Matthias Ginter, who is a centre-back but is expected to start at right-back for Germany.
Oyarzabal starts in a similar position for Real Sociedad in La Liga and should feel right at home in the fixture. He has scored six goals in just nine La Liga appearances so far and has been in good touch in front of the goal, which bodes well for Spain as they desperately need a consistent goal-scorer.
The 23-year-old will have to get past Ginter, who is one of the most underrated defenders in the Bundesliga and can take up any role he's asked to play in the defence. Ginter is a strong, composed defender who has the right skill-set to keep Oyarzabal in check.
#4 Mikel Merino vs Leon Goretzka
The clash between Spain's defensive midfielder Mikel Merino and Germany's box-to-box midfielder Leon Goretzka could prove to be one of the most physical battles on the pitch on Tuesday night, as both players are known for their physical stature.
Merino, another Sociedad player in Enrique's side, has been developing steadily over the last couple of seasons. He is one of the most sought-after midfielders in La Liga, thanks to his timely ball interceptions, aerial prowess and ability to control the ball under pressure.
Though Merino may have only 75% passing accuracy in the league, he averages 4.4 aerial duel wins per game and will add steel to Spain's midfield.
Goretzka has been known for his technical abilities from his days at Schalke, but his physical transformation recently has opened a lot of doors for him. He is now one of the best box-to-box midfielders in Europe due to his improved endurance and strength. The 25-year-old has become of the key members of the national team and was crucial in their win over Ukraine.