Ronaldo's second-half introduction certainly sent a surge through United - and dispelled any doubts the summer transfer saga with Real Madrid would affect his popularity.
But United could come no closer than a late Jonny Evans diving header that bounced back off a post as their 12-game winning streak on home soil in the competition was brought to an end, the Yellow Submarines almost sinking Sir Alex Ferguson's men altogether when Guille Franco hit the woodwork as well.
The litany of woe began after just five minutes when Owen Hargreaves curled over a corner that Diego Lopez completely misjudged to leave Rio Ferdinand an empty net to steer the ball into.
Unfortunately for United, Ferdinand succeeded only in prodding the ball back in the general direction it had come from.
Then it was Wolfgang Stark's turn to fail. The German official may have been deceived by Park Ji-sung falling outside the area and then opting not to make any significant protest. But there was no doubt Sebastian Eguren caught the South Korean inside the box and a penalty should have been given.
Ferguson resisted an obvious temptation to bring on Ronaldo at half-time.
But some intricate passing involving Wayne Rooney and Fletcher, plus an up and under from Nani which Lopez collected with some difficulty, failed to convince the United boss a goal was going to come so, to huge cheers, Ronaldo was told to get stripped.
The winger was still waiting to be introduced when Villarreal almost hit their hosts with the ultimate sucker punch. Finding space just outside the box, Angel Lopez crossed for Franco. The striker flicked the ball goalwards with the back of his heel and watched in agony as it bounced back of the post.
With Ronaldo - and Anderson - on the field, United were transformed. The Portugal winger managed a header that floated wide before Evans hit the post but it was a familiar tale of disappointment for the hosts in front of goal this season.