Messi scored once yesterday while Real Madrid striker Gonzalo Higuain hit a hat-trick to give new coach Alejandro Sabella a triumphant start in his first competitive match in charge.
Argentina's Spanish club influence was completed by Angel Di Maria setting up two of the goals for his Real Madrid teammate Higuain.
"It was important to get off on the right foot and we did just that," said Higuain.
"I liked a lot of what we did tonight. Now we have to keep this up."
The 1978 and 1986 world champions, rebuilding after a poor Copa America which saw them exit in the quarter-final, were ahead after eight minutes at Buenos Aires' Estadio Monumental where they haven't lost a World Cup game for 18 years. Di Maria slipped in a pass to Higuain who drove the ball high into the net past Claudio Bravo in the Chile goal.
Messi then scored his 18th international goal in his 63rd appearance in the 26th minute when he was released by a fine pass from Higuain before beating Bravo with a low shot from the edge of the box.
Chile, who were without key players Alexis Sanchez and Gary Medel through injury, came close to cutting the deficit in the 42nd minute when Humberto Suazo was unfortunate to see his effort deflected wide by the foot of Pablo Zabaleta.
Di Maria set-up the third for Argentina in the 51st minute when he found Higuain with a smart cross which his Real Madrid teammate converted with a shot on the turn.
Nine minutes later Matias Fernandez pulled one back for Chile before Messi teed-up Higuain for a his hat-trick in the 63rd minute after a poor Bravo clearance.
Copa America winners Uruguay got their qualifying campaign off to the perfect start as they beat continental outsiders Bolivia 4-2 in Montevideo.
With Argentina rebuilding and Brazil having qualified automatically for the tournament that they will host, Uruguay came into the marathon South American campaign as favourites.
The combination of an early kick-off and miserable weather conditions meant there was a sparse crowd at the Centenario stadium, but Oscar Tabarez's side did not disappoint the fans who did turn out.
Uruguay took the lead with just three minutes on the clock when Liverpool striker Luis Suarez netted from inside the six-yard box after the Bolivian defence had failed to deal with a Diego Forlan corner.
Bolivia came up with a shock equaliser when Rudy Cardozo clipped the ball over goalkeeper Fernando Muslera and into the net off the far post.
La Celeste, World Cup winners in 1930 and 1950, reacted well to restore their lead before the half-hour mark when captain Diego Lugano rose highest to head a Forlan free-kick past Carlos Arias in the Bolivia goal.
And it was 3-1 before the interval with Napoli's Edinson Cavani diving to head home a right-wing Maxi Pereira cross at the far post.
Bolivia are not the same side when they leave the rarefied atmosphere of their La Paz home and they could have conceded a fourth shortly after when Forlan saw his header from close range saved by Arias.
The Inter Milan player needs just one goal to become Uruguay's all-time leading scorer, but he will have to wait at least another few days as it was Lugano that got his second and his team's fourth from close range midway through the second-half.
Marcelo Martins pulled another goal back for the visitors from the penalty spot. Elsewhere on Friday, Ecuador defeated Venezuela 2-0 while Peru were facing Paraguay later.