United rarely found top form on the night and were always second best after Eto'o broke the deadlock just ten minutes into the game.
Rio Ferdinand was fit to take his place at the heart of the United defence, while Ryan Giggs started in place of the suspended Darren Fletcher in midfield.
Injuries and suspensions forced Barca to move Yaya Toure back into defence, with skipper Carles Puyol moving across to right-back.
United came close to making a perfect start as Cristiano Ronaldo fired in a low free-kick which keeper Victor Valdes spilled and only a Gerard Pique block prevented Ji-Sung Park from knocking home the rebound.
Ronaldo then tried his luck with two shots from distance, before Barca took a shock lead with ten minutes on the clock.
Andres Iniesta broke from midfield and played in Eto'o, who stepped inside Nemanja Vidic and drilled the ball past Edwin van der Sar at his near post.
Ten minutes later Messi picked up the ball 30 yards out on the right and rifled a left-foot shot a couple of feet over the United bar, with van der Sar struggling to cover.
The rest of the first half saw few openings for either side, but Barca retained the upper hand for much of the time, being content to retain possession and keep United on the back foot.
Barca started the second half at a rate of knots, with Thierry Henry forcing a smart save from van der Sar soon after the restart.
Soon after Iniesta was brought down by sub Carlos Tevez 20 yards from goal and Xavi's excellent effort curled round the wall and came back off the post with van der Sar diving desperately to cover.
United then stemmed the Barca flow and responded a couple of times, but never came close to extending Valdes, who was enjoying a surprisingly quiet evening in the Barca goal.
Twenty minutes from time it was game over as Xavi had time and space to play in a superb cross from the right and Messi was unmarked at the far post to head home from eight yards.
Puyol and Iniesta threatened to add a third goal as the clock ticked away, with the final whistle allowing Barca coach Pep Guardiola to celebrate a league, domestic cup and European treble in his first season in charge at the Camp Nou.