With regular number one Manuel Almunia sidelined with a virus and Poland international Lukasz Fabianski still recovering from knee surgery, the Italian will be thrown into the cauldron of the Stade Maurice Dufrasne as Arsenal's senior goalkeeper.
Despite just one Premier League match, against Stoke City last season, and a couple of games while on loan at Barnsley under his belt, Wenger is backing the 21-year-old to seize his opportunity.
"It is a big challenge for a young boy to come into a Champions League game with such a big pressure, especially away from home," said Wenger. "When you look at the stadium, it will be quite a difficult atmosphere."
Arsenal paid Italian side Atalanta £350,000 compensation for Mannone, then 17, four years ago.
Wenger will also be without Dutch forward Robin van Persie because of a slight knee problem. Croatia striker Eduardo is free to play following the decision by UEFA to overturn their suspension handed out after the qualifier against Celtic at Emirates Stadium last month.
Wenger said: "I am very happy we have Eduardo back because we have plenty of offensive players who are out. We have [Andrey] Arshavin, [Theo] Walcott, [Samir] Nasri and of course Van Persie.
"Eduardo on top of that would have been too many strikers to have out. That is why I am very happy to have him back. It was a good surprise I must say."
Defensive midfielder Denilson is also sidelined by a minor back complaint, so Czech winger Tomas Rosicky could be in contention having made a long-awaited comeback at Manchester City.
Wenger said: "Everybody in the squad is very happy to have Tomas back, not only because we love him but because he is a fantastic football player. He has a good chance because it is a good opportunity for him."