Mustafi, 25, was sprinting alongside Ramil Sheydaev when he fell to the floor clutching his right thigh.
He was aided from the pitch before being replaced by Matthias Ginter.
"It doesn't look good, it looks like he had torn a ligament".
Germany has never qualified for a World Cup finals before with a 100 percent record.
He will now head back to north London where he will undergo scans to determine the seriousness of the injury.
The trio have helped Arsenal keep four clean sheets in their past four Premier League games and Arsene Wenger will be pained to mix up what was proving to be an effective defensive formula.
It appears nearly certain that Mustafi will be ruled out of Arsenal's remaining games in October, with five fixtures coming up in the coming weeks. "It will be hard to become world champions twice".
Leon Goretzka opened the scoring for the home side before Sheydaev scored a shock equaliser.
Ruediger headed Germany's third goal, two minutes before Goretzka claimed his second, and Emre Can wrapped it up late with a brilliant strike from distance.
Liverpool midfielder Emre Can added the fifth when he smashed home his first worldwide goal with a powerful shot from outside the area.
Sandro Wagner also continued his fine form by scoring his fifth goal in five caps as Germany topped Group C, having already booked their chance to defend the trophy at next summer's World Cup in Russian Federation.