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Messi usually uses his head to send instructions to his feet on how to humble defenders, and the combination brought him a season-high nine Champions League goals and 38 in total for Barca.
The ninth was a looping header over goalkeeper Edwin van der Sar in the 70th minute as Barcelona proved itself the best around by outplaying defending champion United and swinging the pendulum of power back from the English Premier League to La Liga.
"This is the most important victory of my life," Messi said. "When the second goal came that calmed us down a lot."
Samuel Eto'o put the Spanish champion ahead in the 10th minute at Stadio Olimpico and the triumph completed a sweep of titles for 38-year-old Barcelona coach Pep Guardiola in his first season, after wins in the Spanish league and cup. The former Barcelona star, who started as a ball boy at Camp Nou, joins five others who have won the title both as a player and a coach.
"When I won as a player I was young and it was magnificent," Guardiola said of his 1992 triumph at Wembley against Sampdoria. "But now winning the treble at the first attempt is marvelous."
United was chasing its fourth European Cup title, and fourth trophy this season after winning the Premier League, FIFA Club World Cup and League Cup.
But United was thoroughly outplayed by the Spanish side, which has 153 league and cup goals this season.
Xavi Hernandez floated a diagonal ball into the United area to find Messi unmarked, and the 5-foot-7 (1.69-meter) Argentina striker - renowned for his deft dribbling and shooting - used his head to redirect it past Van der Sar.
The loss left Man United manager Alex Ferguson at 25 titles in 23 seasons. He failed to match Liverpool's Bob Paisley's three titles in the competition.
"We started the game brightly. We were confident and we could have been in front," Ferguson said. "We had the ball but didn't use it very well. ... We defended fantastically all season but they were two shoddy goals.
"We didn't play as well as we can, but they are a good team. We have to give them credit. Xavi and (Andres) Iniesta can keep the ball all night. They made it very difficult."
South Korean winger Park Ji-sung became the first Asian to play in a Champions League final. He almost scored for United in the opening minute but his shot was deflected wide after Cristiano Ronaldo's free kick was blocked by the goalkeeper. It was the nearest United came to scoring all night.
The victory also marked the first Champions League title for Barcelona striker Thierry Henry, who was on the losing side when Arsenal lost to Barcelona in 2006.
"Finally, I've been waiting for so long to get this title and now finally today," said Henry, who had been doubtful for the final because of a knee injury.
"The last five minutes were the longest of my life."
United almost went ahead in the opening minute when a needless foul by Yaya Toure on Anderson handed Ronaldo a free kick. His powerful drive was blocked by the hands of goalkeeper Victor Valdes and Park's rebound was deflected for a corner by Gerard Pique.
With Barcelona's dangerous forwards barely getting a touch of the ball in the early stages, there was little danger at the other end until the Spanish champions went ahead with their first attack of the game.
Iniesta started the move with a break through midfield and found Eto'o on the right. The striker cut inside a weak tackle by Nemanja Vidic and poked a low angled shot around Van de Sar.
"I think the credit must go to the good play of the team," Eto'o said. "I think the victory is much more important than the goal."
The goal changed the pattern of the play with Barcelona's stars settling into their confident style of interpassing. United, chasing the score, was unable to create any real danger. Ronaldo wanted to shoot at every opportunity, but fired wide and headed over.
Ferguson reshaped his attack for the second half, sending on a second striker, Carlos Tevez, and later added Dimitar Berbatov. That left United undermanned in midfield and Barcelona continued to create openings.
Barcelona could have added more but Van der Sar saved twice from Carles Puyol and Ronaldo was shown the yellow card for some petulant late challenges on the Barcelona captain.
Meanwhile, 85 police officers were hurt out of 153 overall injuries and 134 people were arrested during celebrations of Barcelona's victory over Manchester United in the Champions League final, police say.
Arrests were made mainly for public disorder, vandalism and disobeying police orders in Barcelona, while 15 other people were apprehended in the Catalan towns of Lleida, Tarragona, Girona, Granollers and Igualada.
Trouble had also flared at previous celebrations in Barcelona earlier this month after the team won the Copa del Rey and then the Spanish league title.