A surprise announcement on Friday morning confirmed Wenger will bring down the curtain on his near 22-year reign as Arsenal manager at the end of the season.
The first game since his announcement comes at home to West Ham on Sunday, with the Premier League a much bigger priority for the struggling Hammers than it is for Arsenal - who have all-but missed out on the top four for a second season in succession.
That is largely down to their abysmal away form, with defeat at Newcastle last weekend leaving the Gunners with just three league wins on the road all season and no points taken away from the Emirates since the turn of the year.
Mustafi was at fault for Newcastle's opener and has made several mistakes this season that have seen his credentials as a top-level player questioned - despite the fact he is a fully-fledged Germany international.
"His confidence is lower," Wenger replied when asked if there was a problem.
"He has played many games and most of the mistakes he made have been post-Europa League games because he was a bit jaded.
"On that front that is part of the fatigue factor which would be the explanation why he had some less good games.
"We are in a job where we can't demand that people, when you make mistakes, say that it's absolutely wonderful. That's part of Arsenal. Like me when I lose games, I have to accept that."
Mustafi joined for a fee in excess of £30million in 2016 but reportedly came close to leaving for Serie A last summer before the decision was taken to retain his services.
Wenger insists the 25-year-old was never likely to leave and backed him to be at the club for the foreseeable future.
"I think so, yes," he replied when asked if he felt Mustafi would be an Arsenal player in the long term.
"He wasn't close (to leaving). He is a young defender who has had ups and downs. I believe overall he has potential. He is one of the guys who is committed and goes for the challenges.
"He is not one guy who hides from the responsibility, so overall he will be a promising defender for the future. Experience helps.
"In this job, goalkeeper and central defender is a job for old people or older people. So overall that plays a part of course."
Join our commenting forum
Join thought-provoking conversations, follow other Independent readers and see their replies