The Barcelona forward's injury keeps him and a number of other Albiceleste stars sidelined as Gerardo Martino's side seeks to exact revenge on Joachim Low's men
The South Americans meet Joachim Low's men this week less than two months after their 1-0 defeat to Germany at the World Cup showpiece in Rio de Janeiro.
Wednesday's clash serves as the perfect opportunity for new Argentina coach Gerardo Martino to make a strong first impression as they build towards next year's Copa America.
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Martino was appointed following the resignation of Alejandro Sabella after the World Cup, but faces the most difficult of tasks if he is to get his tenure off to a winning start.
And Martino and Argentina's hopes of victory in Dusseldorf have been hit by the absence of Messi, who played under the 51-year-old at Barcelona last season and will be out of action due to a hamstring strain.
The 27-year-old has been withdrawn from the squad as a precaution and is not the only the key player unavailable to Martino.
Indeed, Rodrigo Palacio (ankle), Maxi Rodriguez (hamstring) and Ezequiel Garay (leg), all of whom contested the World Cup final, are on the sidelines, while forward Ezequiel Lavezzi is a doubt due to a back problem.
Germany will also be without an array of players that contested the gripping final at the Maracana, with former captain Philipp Lahm, defender Per Mertesacker and all-time leading goalscorer Miroslav Klose all retiring from international football after sealing a fourth world title for their country.
In addition, midfielder Bastian Schweinsteiger and defender Shkodran Mustafi were not considered fit enough to be named in the squad for the game at the Esprit Arena.
Arsenal midfielder Mesut Ozil is also a doubt through injury for Germany, although the hosts will be able to welcome back Marco Reus after the Borussia Dortmund star missed the World Cup due to an ankle ligament problem.
While much will be made of the quick renewal of acquaintances between the two sides, for Germany the game is little more than a prelude to its qualification campaign for Euro 2016, which begins on Sunday against Scotland.