Carles Puyol, Pedro and David Villa, who came on for his first competitive action since breaking his leg last December, also scored to give Barca an immediate advantage over arch-rivals Real Madrid who were held 1-1 at home by Valencia.
World Player of the Year Messi scored a league record 50 goals last season and settled Barca with quick strikes to give them a 3-1 lead inside 15 minutes at the Nou Camp.
Pedro volleyed in a fourth just before the break but the biggest cheer was reserved for Spain striker Villa when he was brought on in the second half and then stroked home the fifth goal near the end.
Spain's all-time leading scorer with 51 goals, broke his left leg at the Club World Cup last December and missed the national team's Euro 2012 triumph as he continued his recovery.
He replaced Pedro in the 74th minute to a huge Nou Camp ovation, and swept a shot inside the far post, after a pullback from Andres Iniesta, to crown his return with six minutes left.
Villa, 30, peeled away to celebrate, pulling off his shirt to reveal a vest with "Impossible without you" written on it above a photo of his wife and children.
"He has suffered a lot, he has had a considerable injury and he is back," team mate Xavi told Spanish television.
"It was a good win but the best news of all is the return of 'El Guaje' ('The Kid'), we have missed him."
Barca were limited in their options going forward in the second half of last season with Villa injured and relied heavily on the goals of Lionel Messi.
"I am happy with the squad we have," new Barca coach Tito Vilanova said after his first league match since stepping up from assistant to replace Pep Guardiola.
"We hope that Villa is back to full fitness as soon as possible because we are missing his goals.
"It is always important to win the first game but perhaps the best news today is the return of Villa.
"The goal will boost his morale and give him confidence. It has removed a weight from his shoulders. It's good for the team that he is back and well."
Although it is only the first round of matches, a two-point advantage for Barca over Real is significant because Jose Mourinho's side only dropped 14 in their 38 games last term on their way to a league record points tally of 100.
The visitors were three goals up in 31 minutes before last season's Europa League and Copa del Rey finalists responded in the second half.
Bilbao's Oscar De Marcos got a goal back just after the break and Mikel San Jose then struck twice to level the scores with 14 minutes to go before Betis finally triumphed late on through Alejandro Pozuelo and Jorge Molina with his second.
In the day's other game, Levante drew 1-1 at home to Atletico Madrid.
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