It could be argued Rooney's struggle for form has been a contributing factor to a stop-start opening that has seen United register four draws from seven matches in all competitions.
Yet that only tells part of the story, which is why Rooney's absence from the team flight to Spain through an ankle injury should have minimal effect.
Of far more importance is defensive solidity, which has been strangely absent for United so far but which they will undoubtedly require on Wednesday if they are to avoid defeat against a side that has shrugged off the summer departures of David Villa and David Silva to become the surprise early-season pace-setters in the Primera Division.
"It is going to be a difficult match," said midfielder Darren Fletcher.
"People might say it is not the same Valencia because they have lost Villa and Silva.
"But as we have seen at Manchester United, when you lose good players others step up to the mark and take on more responsibility.
"They have had a fantastic start."
United, and in particular Rooney, cannot say the same.
Dimitar Berbatov has been the Red Devils' stand-out offensive player so far this season and Michael Owen has scored three times in a week, so there was an argument that Rooney did not deserve to be selected this week anyway.
His ankle niggle has provided a reason for Ferguson to leave him at home, which will allow the 24-year-old a chance to get his mind right following damaging allegations about his private life.
United are yet to offer any firm indication of how long Rooney will be absent for, with his next two opportunities to return coming against Sunderland in the Premier League on Saturday and for England in their Euro 2012 qualifier with Montenegro on October 12.
However, at least by confirming his absence at this early stage, matchday should be relatively free of diversions.
None of this should deviate Rooney's team-mates - also shorn of the injured Antonio Valencia and Ryan Giggs - from their task of avoiding defeat in one of Europe's most impressive stadiums, the Mestalla.
"We have picked up experience of playing in Europe and we have confidence," said Fletcher.
"We know how to cope with the travel and the different styles of play.
"Against Spanish sides, keeping the ball is key.
"If you give the ball away cheaply, you might not see it for a few minutes and they will punish you."