Messi limped off with an injury for the third time this season yesterday 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.
"In the first half hour we played the game where Betis wanted us to play," he said.
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"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.
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.