After his brilliant four-goal Champions League haul against Arsenal on Tuesday, the Argentina forward struck in the 33rd minute at the Bernabeu before Pedro doubled the visitors' lead in the 56th with a clinical left-foot strike.
Both goals were created by Barca's Spain midfielder Xavi, the first when he chipped the ball to Messi over the Real defence and the second when he sent Pedro clear to finish with a low strike beyond Iker Casillas.
La Liga top scorer Messi twice came close to adding to his 27 goals of the campaign and Barca goalkeeper Victor Valdes was rarely troubled as Real struggled against the European champions' slick passing game and dominance of possession.
The victory puts Barca on 80 points with seven matches left and leaves the big-spending Madrid club, who have 77, facing a season without silverware after their exits from the Champions League and King's Cup.
After reaping an unprecedented six trophies in 2009, Barca coach Pep Guardiola becomes the first manager of the Catalan club to claim four straight wins in the "Clasico."
With a two-legged Champions League semi-final against Inter Milan to come later this month, he also has a chance rub salt into Real's wounds by winning a second consecutive European title in May's final at the Bernabeu.
"We came to play the leaders who have won 15 out of 15 matches here this season so we are delighted," Guardiola said at a news conference.
"We won comfortably," he added. "It wasn't brilliant but you have to bear in mind we were playing a great team."
DISGUSTED FANS
After a tense opening to a contest Marca sports daily had dubbed "the match of the millennium," Messi squared the ball to Xavi and he lifted a delicate chip over the static defence.
Timing his run to perfection, Messi controlled the ball on his chest and dinked a shot past Casillas into the net.
Striker Gonzalo Higuain fluffed a chance to put the hosts level in the 41st when a mistake by Gerard Pique put him clear and he did little to boost his chances of starting for Argentina at the World Cup by slicing his shot into the crowd.
Xavi again underlined why he will be crucial to Spain's bid for a first World Cup triumph in South Africa when he carved open the Real defence with a superb through ball and Pedro raced into the area to double Barca's lead.
Although the Catalans did not match their 6-2 thrashing of Real in last season's Clasico in the Spanish capital, which effectively clinched the title, Saturday's performance was no less emphatic.
Real coach Manuel Pellegrini threw on veterans Raul and Guti to try to spark the team into life but they faded badly as the final whistle drew near and the disgusted home fans began to head for the exits well before the finish.
The Barca players rejoiced in an ecstatic huddle at the final whistle and the small knot of travelling fans high up in the stands celebrated wildly.
Pellegrini said his players had appeared anxious but noted it was unusual to restrict
