It took Barca 44 minutes to break down the Betis defence, but it was a goal worth waiting for. Andrés Iniesta teased the Betis defence before slipping a pass to Messi which the Argentina striker nonchalantly flicked over Casto.
Messi rolled in another at the second attempt on 62 minutes then burst through to complete his hat-trick (73). Pedro Rodríguez made it four and Seydou Keita nodded in number five.
In the other game, holders Sevilla came from 3-1 down to draw with at Villarreal. Villarreal scored two goals inside the first 30 minutes through a volley from Cani and a deflected Giuseppe Rossi shot before Álvaro Negredo pulled one back for Sevilla. Marco Ruben nodded Villarreal 3-1 up only for Negredo to head in on the hour and allow Alexis (88) to sweep in the equaliser.