Messi limped off with an injury for the third time this season after pulling up with a hamstring problem as he tried to accelerate just 20 minutes in.
However, any worries Barca could struggle without their star man were extinguished by two goals in as many minutes when Neymar rolled home Cesc Fabregas’s pass before Pedro Rodriguez’s wonderful individual effort doubled the advantage.
Fabregas added the third from Martin Montoya’s cut-back and the former Arsenal captain doubled his tally when he headed home 11 minutes from time before Jorge Molina’s stoppage time penalty pulled a goal back for Betis.
And Barca boss Gerardo Martino was happy with how side responded after a difficult opening half hour.
“In the first half hour we played the game where Betis wanted us to play,” he said.
“Their pressing was quite intense, but we then started to find spaces in behind their defence.
“The same thing happened at the beginning of the second-half and the fact they got a goal was deserved for their performance, but overall I think we played a very intelligent match.”
Despite lying bottom of the table, it was Betis who started the brighter as Barca were thankful to Victor Valdes for making fine saves from Molina and Juan Carlos.
Messi was then replaced by Andres Iniesta but even in his absence Barca began to exploit Betis’s high defensive line and both Neymar and Pedro should have scored but their weak efforts were held by goalkeeper Guillermo Sara.
The opener arrived on 35 minutes as Fabregas sprung the Betis offside trap from Alex Song’s pass and squared for Neymar to roll home his fifth Barcelona goal.
Moments later Pedro ran from inside his own half before curling a fine finish high past the helpless Sara.
Betis also started the second period strongly and Nono rattled the post with a drive from distance.
However, Barca were still getting in behind the Betis defence at will and after Neymar twice failed to beat Sara when one-on-one with the keeper, Montoya squared for Fabregas to tap home the third on 63 minutes.
Fabregas also had his fifth goal of the campaign when his downward header crept in off the inside of the post, but he too had to be withdrawn late on with a knee injury.
Molina converted from the spot after Dani Alves had brought down Javier Matilla at the death, but it was scant consolation for Betis who remain rooted to the foot of the table.
Barcelona now have their biggest lead of the campaign at the top of the table as Atletico Madrid dropped points for just the second time this season with a 1-1 draw at fourth-placed Villarreal.
Mario’s own goal less than two minutes in gave Atletico the perfect start but Villarreal went on to dominate the game and were rewarded 12 minutes form time when Juanfran also turned into his own net under pressure from Ikechukwu Uche.
However, despite losing ground in the title race, Atletico boss Diego Simeone was satisfied with a point given that his side were far from their best.
“We were facing very strong opponents that are playing very well and are in good form,” he said.
“Defensively we did very well. We didn’t have clear chances but we did control the ball.
“In the second-half we improved a bit but it is an important point against a rival for the Champions League positions. I congratulate the players for the effort they are putting in.”
Villarreal coach Marcelino also lauded his players’ performance but was disappointed not to have taken all three points.
“We played a great game against very good opponents that went ahead in the second minute.
“We are very proud of these players, their attitude and their play. We had absolute control and it was a shame we weren’t more precise on some of our chances.”