Although United could take some small consolation from the knowledge they were more effective than that 2009 letdown in Rome and even managed to level Pedro's first-half strike through Wayne Rooney, once again the better team won.
On the ground where the Catalans lifted their first European Cup, Messi also laid his personal ghost to rest, scoring his first goal for Barcelona on English soil, belting home what proved to be the winner nine minutes into the second half.
Villa curled home an equally splendid third with just over 20 minutes to go to set the seal on Barcelona's fourth Champions League win and end all arguments about their right to be regarded among the truly great teams that have ever played the game.
It was a gut-wrenching night for United manager Sir Alex Ferguson, who started it by making one of those brave decisions for which he is so renowned. Not even finding a place on the bench for his record signing and top scorer, Dimitar Berbatov, was a big call.
United could not have made a better start either.
Park Ji-sung set the tone, nipping in to whip the ball away from Dani Alves.
Just as Jack Wilshere advised, the white shirts got right in Barcelona's faces, pressing them, allowing no room for them to settle.
Unlike two years ago, Ferguson's team did not create a clear-cut chance.
However, former Red Devil Gerard Pique was very fortunate to get away with a back pass to Victor Valdes, when his goalkeeper was much closer than he realised.
With Javier Hernandez closing in, Valdes scrambled the ball away.
It was the template United needed to follow. To have done it for the entire 90 minutes would have required additional lung capacity. And once Barcelona got into their stride, they were relentless.
For once Ryan Giggs looked every one of those 37 years as Xavi and Andres Iniesta flashed around him, holes appearing everywhere.
Pedro prodded wide at the near post. Villa hit exactly the same point in the advertising hoarding with a 20-yard effort that had Edwin van der Sar scrambling.
If there was one consolation, other than Nemanja Vidic's colossal performance at the heart of their defence, it was that United had prevented Messi running at them from deep.
Unfortunately, he soon started doing it, his close control near-perfect, as was a Vidic lunge to stop the world's best player as he was about to break clean through.
It was just a matter of time. Another hole for Xavi to chase into. He looked. He looked again. He rolled the ball to Pedro, who beat Van der Sar with ease.
Barcelona coach Pep Guardiola sat back, sensing United would not be able to respond. His opposite number urged more from his team, particularly Antonio Valencia.
The Ecuador wide
man was not at his best. However, it was Rooney who needed a performance on the biggest stage, having failed so miserably at the World Cup.
And it was Rooney who delivered at the end of a move which saw the Premier League champions carve Barcelona open with their own game.
A quick pass from Fabio to Rooney, to Michael Carrick, to Rooney, to Giggs, to Rooney, into the corner from 15 yards. Simple.
Football is never that. Not at this level, and not when Messi is involved.
You had to feel sorry for United. Barcelona were back into their rhythm almost immediately after the break, the concentration required to always be in the right place at the right time phenomenal.
After more stoic defending, Iniesta rolled a pass to the Argentinian, a worthy heir to Diego Maradona.
Offered a couple of yards to dart into, he did exactly that, then beat Van der Sar with a 20-yard shot that required barely any back lift, the veteran Dutchman unable to get down to it.
Vidic was on hand to hack away when Van der Sar spilled Messi's next effort, although, playing in his fifth final, the former Ajax man redeemed himself when he brilliantly turned away a Xavi shot that would have ripped away any hope.
By introducing Nani for Fabio and pushing Valencia to full-back, the United boss was attempting to push Barcelona towards their own goal.
Before the strategy could be applied, Nani committed suicide by gifting the ball to Messi by the touchline.
In attempting to atone for his error, the winger made it worse.
Sergio Busquets quickly laid the ball off to Villa, who took one touch before curling a sublime shot into the top corner.
From that hammer blow, there was no way back.