Villa will face CSKA Moscow in Russia on Thursday for the second-leg after their first leg ended in a 1-1 draw last week.
O’Neill is ready to leave several key players at home, in order to prepare for the following Premier League games against Stoke and Manchester City.
Skipper Gareth Barry admitted: “This is a difficult one for the manager.
“If you are looking at Stoke as the priority it might be vital, after playing two games in four days last week, that a few players get some rest.”
Aston Villa are still fourth in the Premier League, six points ahead of Arsenal.