The Borussia Dortmund star was clearly in pain after twisting his left ankle and had to be replaced by Lukas Podolski - a concern with the World Cup less than a week away.
The Borussia Dortmund attacker had to be helped from the field by medics after suffering an apparent ankle injury just a minute before the end of the first half of the game in Mainz.
Reus had been left screaming on the ground in agony following a heavy challenge from Armenia midfielder Artur Yedigaryan.
Germany has yet to confirm the exact nature of the injury, but Reus' withdrawal will be of major concern to coach Joachim Low.
The 25-year-old had been considered a certain starter for his country's World Cup opener against Portugal on June 16.
Low will perhaps, though, take some consolation from the fact that Reus' replacement against Armenia, Lukas Podolski, proved his enduring worth to the national team by setting up the opening goal for Andre Schurrle.