O'Neill has omitted Gareth Barry, Brad Friedel, Emile Heskey, James Milner, Ashley Young, Gabriel Agbonlahor, Carlos Cuellar and Stiliyan Petrov from his 19-man squad for the trip to CSKA Moscow on Thursday.
CSKA enjoy a slight advantage after recording a 1-1 draw at Villa Park in the first leg, but O'Neill has decided to rest his star assets as the club look to succeed in Russia.
Villa are hoping to qualify for next season's UEFA Champions League by finishing in the top four of this term's Premier League, and O'Neill has reiterated his confession that domestic matters take priority.
He said: "We want to keep momentum going in the Premier League - an opinion I am sure Villa fans would echo.
Difficult decision"But we don't really have the size of squad that Manchester United, Liverpool, Chelsea and Arsenal can call on. That's not being defeatist - that's just being realistic.
"We have to try and please Villa fans but I am sure they would think that the Premier League, which can help drive you into the Champions League, is the Holy Grail."
But O'Neill admits that it is a difficult decision to downgrade the Uefa Cup after Villa - who currently sit fourth in the league - battled through the pre-season Intertoto Cup to earn a spot.
"The irony is we broke our necks to get into Europe," he added.
"It seems strange I know but had we been seventh, eighth or ninth, let's say, in the table, it would have been a different outlook.
Complaint"Chasing a top-four spot, though, to get you a place in the Champions League, is everything."
Villa striker John Carew - who is a member of the squad travelling to Moscow - has backed O'Neill's tactical call.
"Some of the players have had a lot of games and are a bit tired," the Norwegian told Sky Sports News.
"We still have a lot of important games to go so I think it is natural to divide the games among the players."
Carew has been working to regain full fitness following a three-month back complaint and he has been forced to make do with a place on the bench in recent weeks.
But the former Lyon and Valencia man is confident he can soon work his way ahead of either Gabriel Agbonlahor or Emile Heskey in O'Neill's pecking order.
"I hope to see myself playing all the games soon," he concluded.