Mustafi, 25, went down clutching his leg during the first half of Germany’s World Cup qualifier against Azerbaijan before being carried off the pitch.
He will undergo tests upon his return to north London but is almost certain to miss Saturday’s Premier League clash against Watford.
Germany coach Joachim Low said: “It doesn't look good, it looks like he had torn a ligament.
“We're waiting for a full diagnosis, but it looks like he will be out for a while.”
It is a big blow for Arsenal boss Arsene Wenger, who has favoured a three-at-the-back formation since the end of last season.