The Argentine World Player of the Year, who is up against team-mates Xavi and Andres Iniesta for the FIFA Ballon d'Or on Monday, swept in a free-kick in the 51st minute, having already set up striker David Villa for the opener.
Iniesta made it 3-0 in the 80th and almost immediately Messi's driving run led to the ball breaking to Pedro, who lifted the ball into the net for the fourth.
Barca extended their unbeaten streak to 26 matches in all competitions but Spain striker Villa preached caution.
"We may be on a good run but we have a team like Real Madrid pushing close behind us," he told Spanish television. "There is still a long way to go."
Villa raced on to Messi's pass after 26 minutes and squeezed his shot under Daniel Aranzubia to put Barca ahead.
Messi claimed his 18th goal of the campaign with a freekick which curled round the wall and into the top corner after the re-start, and Iniesta killed off the game, running across the edge of the area before firing inside the far post.
After Pedro's cool finish, Messi almost grabbed a second but Aranzubia did just enough to deflect his shot wide.
Asked who would win the Ballon d'Or, which will be awarded for the world's best player on Monday, Villa said: "In the dressing room the general opinion is that it doesn't matter. For us, it is good enough that the winner is already among us."
KANOUTE DOUBLE
Earlier, two goals in three minutes from Luis Fabiano and Frederic Kanoute helped Sevilla fight back to win 3-2 at promoted Real Sociedad.
Sevilla's fourth straight victory in all competitions helped lift Gregorio Manzano's improving side up to ninth with 26 points from 18 games.
They are behind Athletic Bilbao on goal difference after the Basque side drew 1-1 at Malaga.
Mali striker Kanoute volleyed Sevilla level in the 25th minute, soon after Diego Rivas had opened the scoring at Anoeta, but Joseba Llorente put the home side back in front with a breakaway goal after hesitant defending just before halftime.
Brazilian striker Fabiano poked the ball home from close range after a corner in the 63rd to level the scores again and Kanoute fired in a off the post soon after to seal the win.
Bilbao's Javi Martinez headed a 93rd-minute equaliser in off the post to deny Malaga at the Rosaleda.
Argentina defender Martin Demichelis, one of four new Malaga signings on show, had marked his league debut with a glancing header from a corner in the 81st to give the hosts the lead.
Malaga remain in 16th place with 17 points, now four points above the relegation places.
