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 for Tuesday's match in Greece.
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.
Manager Arsene Wenger said the 2-0 Premier League defeat to Swansea last weekend, which left Arsenal 10th in the table, changed his plans for the Olympiakos match.
"Saturday's defeat affects the thinking for Olympiakos. There are many players who need a rest, because they are on the verge of getting injured. Some played with knocks against Swansea," the Frenchman said in his regular email to Arsenal supporters.
"It's important that we do well in Greece but, away from home, I'm not too concerned. We look like we play a little bit with the handbrake on at home. It's not fluent. There might be a psychological component in there as well.
"I knew Swansea were a good side and before the game I was concerned that we could be a bit jaded because we had many players who had played a lot of hard games recently. But we were guilty of losing the game at the moment when we should not have lost it."
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.
"Some players needed a rest because they were a bit on the fringe of injury, and some players are injured," Wenger told the club website.
"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's last visit to Olympiakos's Georgios Karaiskakis Stadium 12 months ago ended in a 3-1 defeat for the North London side. They overcame the Greek side by the same margin at home in October.
