Goals from Pedro, Lionel Messi and David Villa secured a deserved victory for the Catalan magicians after England international Wayne Rooney had raised United's hopes with a well-taken first-half equaliser.
The star of an electrifying team performance was Argentinian striker Messi, the 23-year-old maestro whose brilliant effort on 54 minutes saw him equal Ruud van Nistelrooy's record of 12 goals in a single Champions League campaign.
It also took Messi's tally for the season to an astonishing 56 goals in 62 games for club and country, and propelled Barcelona towards their fourth victory in club football's most prestigious competition.
Sir Alex Ferguson's United had been determined to avoid a repeat of the 2009 final in Rome, where Pep Guardiola's side had struck early before going on to clinch a 2-0 win at the Stadio Olimpico.
Yet despite a bright opening United were ultimately handed a defeat that was just as emphatic as their loss two years ago, with the Spanish champions revelling in the wide open spaces of Wembley.
United, lining up in an aggressive 4-4-2 formation, had harried Barcelona relentlessly in the early exchanges as they sought to prevent the Catalans from settling into their flowing passing rhythm.
But it was not long before Barcelona found their feet and United were to spend much of the opening half an hour, and the match, firmly on the back foot.
Villa shot wide after being picked out by Messi on the edge of the area and moments later Pedro went close after Xavi and Gerard Pique combined menacingly.
A jinking run by Messi set alarm bells jangling in the Manchester United defence before the striker threaded a lovely pass to Pedro only for United skipper Nemanja Vidic to slide in with an important block.
United had Vidic to thank for another superb piece of defending shortly afterwards, the Serbian judging his tackle brilliantly to deny Messi.
But on 27 minutes, Barcelona's relentless pressure finally reaped its reward. An exquisite pass from Xavi struck with the outside of the boot picked out Pedro and the winger coolly clipped his shot beyond van der Sar.
At that point Ferguson must have been fearing a repeat Rome.
But crucially, United were able to find an equaliser within seven minutes.
Rooney combined passes with Michael Carrick out wide on the right before racing towards goal. Another one-two with Ryan Giggs, looking perilously close to off-side, and Rooney was in space.
The England international took his time and swept in a curling shot beyond Victor Valdes to round off a wonderful move.
The goal clearly rattled Barcelona, but the Catalans were soon threatening again. Messi went on a surging run and picked out Villa but then just failed to control his team-mate's return pass and United breathed again.
United started the second half positively but again Barcelona were swiftly on top as the warning lights were flashing again.
A fine save from van der Sar denied Dani Alves after the Brazilian was played in by Andres Iniesta before Vidic headed away Messi's follow up shot.
But on 54 minutes Barcelona were back in front.
Messi gathered the ball 25 yards out, and with Patrice Evra standing off fatally, the Barca talisman buried a thunderous low shot beyond van der Sar.
With Barcelona firmly on top it was left to Villa to apply the coup de grace on 69 minutes.
Messi embarrassed Nani before racing down the right flank. When Nani then failed to clear again, Messi found Sergio Busquets who passed to Villa who curled into the top corner.
As the seconds wound down, Guardiola could even give a run out to captain Carles Puyol, surprisingly left on the substitutes bench amid concerns over his fitnesss.
Barcelona: Victor Valdes, Dani Alves (Carles Puyol, 88), Javier Mascherano, Gerard Pique, Eric Abidal, Xavi Hernandez, Sergio Busquets, Andres Iniesta, Pedro Rodriguez (Ibrahim Afellay, 90), Lionel Messi, David Villa (Seydou Keita, 86).
Manchester United: Edwin van der Sar, Fabio da Silva (Nani, 69), Rio Ferdinand, Nemanja Vidic, Patrice Evra, Antonio Valencia, Michael Carrick (Paul Scholes, 77), Ryan Giggs, Park Ji-sung, Wayne Rooney, Javier Hernandez.