The Greeks have lost twice at the Karaiskakis Stadium in the last four years - and the Scot dismissed claims that Tuesday night's first leg in Athens will be a walk in the park for his squad.
"It will be far from easy," the United boss said. "Olympiakos came through a difficult group with Benfica, Paris Saint-Germain (and Anderlecht).
"They have a great home record so it will be a difficult night."
Rooney and van Persie have scored 26 goals in 50 matches between them this season with the England forward also the European competition's most creative player in the group stages, with six goal assists.
"They're both vital to a lot of the things we do," Moyes added. "They're both excellent players. Our record with them is far better than our record without them, that's for sure.
"Both have had injuries, Robin much longer than Wayne, and both have got themselves back into shape. They're both goalscorers and they're scoring goals, which is great for us. That's why they're top players - they score in big games and make the big moments.
"Robin's a fantastic player, one of the best goalscorers in world football. As the manager said, we have a good record when we play together. Unfortunately we had injuries at a similar time this season. Hopefully we can both stay fit and help us win games."
Rooney concurred with his manager and added: "If we're both playing, then we'll score goals, that's for sure.
"But we also have other forwards who can come in and do a good job. It's important we play well - then that will help other players around us play well too."