Messi scored all the goals in the 3-0 win over Atletico Madrid at Camp Nou as the defending champions opened up a 10-point lead over Real Madrid who face Real Sociedad on Sunday.
Argentine magician Messi waltzed through the Atletico defence to give Barcelona the lead in the 17th minute and, after wasting a further chance, he pounced again in the 28th minute.
Atletico came out of their shell at the start of the second half but it was Barcelona who had the cutting edge with Messi scoring again from close range 11 minutes from time.
"We wouldn't be were we are if it wasn't for Leo in our team," said Barcelona coach Pep Guardiola of his Argentine superstar.
"Without him we wouldn't have won so comfortably. You always need to have players who can do something different.
"Real Madrid won 15 beacause they had Di Stefano. We have now won 16 because we have Messi."
Atletico coach Quique Sanchez Flores was full of praise for Messi.
"He is the best player I have seen - the Di Stefano of the 21st century. It was an amazing performance from Barcelona, they are the number one side and have the capacity to hypnotise the opposition."
Real Madrid now face the huge task of clawing back the points difference on Sunday.
"We are all working in the same direction and we are relaxed ahead of the game," said Real coach Jose Mourinho.
"Real Sociedad are a dangerous team who come without fear of relegation. They are a stable side and we have to respect them."
Earlier Saturday, a fine Valmiro Valdo finish gave Levante a shock 1-0 win in their derby clash with Champions League-chasing Villarreal.
Struggling Levante were given little hope going into the game against third-placed Villarreal, who had not been beaten at home since May last year and had only drawn one game this season against Valencia.
Levante got the only goal of the game two minutes into the second half with Valdo rounding the keeper and then sliding the ball home with aplomb.
Athletic Bilbao leapfrogged Espanyol into fifth place with a commanding 3-0 victory over 10-man Sporting Gijon, their fourth on the trot.
The Basque side took full advantage of Espanyol's 3-2 defeat away to Almeria and were always in control.
Defender Gregory Arnolin conceded a penalty after 15 minutes and was given his marching orders for his second yellow card. David Lopez set Athletic on their way from the spot before further goals from Gaizka Toquero Fernando Llorente.
Espanyol crashed to a second consecutive defeat in a calamitous match for keeper Carlos Kameni.
Almeria found themselves two goals up inside just six minutes with Marcelo Silva heading home with ease after the keeper came off his line and then Kalu Uche exposed Kameni at his near post.
Hernan Bernadello fired home a deflected shot to add to the keeper's misery.
Espanyol launched a comeback but goals from Juan Verdu and Alvaro Vazquez proved to be just consolations.
There was a 1-1 stalemate in the relegation clash between Zaragoza and Racing Santander.
Christian Fernandez put Racing ahead with Sad Boutahar equalising.
Adrian Colunga scored a brace as Getafe cruised to a 4-1 win over Deportivo La Coruna.
Nicolas Miku and Pedro Rios hit home the other goals while Ivan Riki found the net from the penalty spot for the visitors.
Mallorca brought a run of three straight defeats to an end with a 1-1 draw with Osasuna when Chori Castro cancelled out Miguel Flano's opener.