Midfielders Santi Cazorla, Jack Wilshere and Mikel Arteta, forwards Lukas Podolski and Theo Walcott as well as defender Per Mertesacker were all missing from Arsenal's 18-man squad named to travel to Greece for Tuesday's match.
Wojciech Szczesny, Thomas Vermaelen, Alex Oxlade-Chamberlain, Aaron Ramsey, and Gervinho will be surrounded by fringe and youth team players, five of whom are yet to make their first-team debut.
"Some players needed a rest because they were a bit on the fringe of injury, and some players are injured," Wenger told club website (www.arsenal.com).
"When I count the injured players I speak about Podolski and Walcott. We needed to rest Wilshere, 100 percent, and Cazorla, Arteta and Mertesacker played many games recently. They have been rested.
"It is [to avoid fatigue], and we have one luxury, that we can do it. But we have as well one necessity, to win the game tomorrow night. I tried to find the right balance between resting some players and as well having a competitive team tomorrow night."
Arsenal have already guaranteed their passage through to the last 16. They can top Group B if they win and German side Schalke, who lead the English club by one point, draw or lose against French champions Montpellier.
Despite a weakened side Wenger will be hoping his 150th Champions League match in charge as coach ends in glory, however Arsenal's last visit to Olympiakos's Georgios Karaiskakis Stadium 12 months ago ended in a 3-1 defeat for the north London side.
Arsenal overcame the Greek side by the same margin at home in October.
Swansea City striker Miguel Michu condemned Arsenal to a fourth Premier League defeat on Saturday when he scored twice to leave Wenger's side 10th in the table as their worst start to a domestic season under his reign continued.
Squad: Wojciech Szczesny, Thomas Vermaelen, Tomas Rosicky, Alex Oxlade-Chamberlain, Aaron Ramsey, Sebastien Squillaci, Francis Coquelin, Andrey Arshavin, Carl Jenkinson, Gervinho, Marouane Chamakh, Martin Angha, Zak Ansah, Sead Hajrovic, Jernade Meade, Elton Monteiro, James Shea, Chuba Akpom