The reigning Spanish and European champions appeared to be in for a tough evening when they fell behind to Pablo Piatti's ninth-minute volley, but instead snapped into life and went into the interval ahead after Messi struck twice.
He doubled his tally in the second period to take his season total to 43 and close in on Cristiano Ronaldo's position as top goalscorer in La Liga, before substitute Xavi capped his return from injury by adding a fifth at the death.
Though the Catalonians remain 10 points behind Jose Mourinho's rampant Real Madrid after the weekend's action, the win extends the gap between themselves and third-placed Valencia - who lost Miguel to injury during the first half - to 11 points.
The hosts began the game full of beans and roared on by their support, and when Messi and Cesc Fabregas fashioned early chances while David Albelda collected his 13th yellow card in 25 appearances by bringing the Argentine down in the fourth minute, the game looked like it may be one-way traffic.
But the visitors timed their strides forward meticulously and after just nine minutes struck gold courtesy of a superbly menacing early cross from the right by Sofiane Feghouli which compelled goalkeeper Victor Valdes to mis-judge a run out of goal to claim.
Piatti, however, had no such issues with his arrival into the area after shaking off young right-back Martin Montoya and volleying home the opener.
Fortunately for Pep Guardiola’s side, going behind woke up the sleeping giants and Pedro’s cut inside from the left at the culmination of a speedy counter deserved a better finish than the straightforward effort sent straight into the arms of Diego Alves.
The Tenerife-born forward did better after 22 minutes when he stole a yard on Victor Ruiz and sent a low cross towards Messi which Adil Rami could only poke slightly further away from the world player of the year.
Not to be deterred, Messi latched onto the loose ball and from an extremely tight angle, managed to squeeze the equaliser inside the far post.
Things went from bad to worse for Unai Emery’s troops when they lost Miguel to an injury in the moments leading up to the goal, and then went behind five minutes later.
After Ruiz had done well to end a Messi run into the box, Andres Iniesta kept the attack alive with an inch-perfect through pass out to the left, meeting the overlapping run of Eric Abidal for the Frenchman to cross for Messi to finish at the second attempt with Alves unable to hold onto the first stab at goal.
Alves recovered from the error to deny Messi a first-half hat-trick as well as efforts from Sanchez and Fabregas, before the former Arsenal lynchpin came within inches of scoring a goal of the season contender only for his scissors kick finish from Iniesta’s wonderful chipped pass over the defence to rattle the bar.
The hosts did not let the half-time break cool off their advantage, coming straight out of the blocks and further testing Alves through Sanchez and Fabregas.
As the hour mark approached, Iniesta came within inches of curling a lovely effort into the far top corner before the impressive Montoya’s impeccable cross met the head of Messi, only for Alves to tip the effort onto the crossbar.
Feghouli, arguably the away side’s biggest attacking threat, kept his head up amidst the Barca blitz and himself was only denied by a good stop from Valdes on 67.
But it was not to be Valencia’s night, and the margin became insurmountable five minutes after Alba’s protests went in vain courtesy of the home team’s very own impact sub.
Academy product Cristian Tello caused problems from the left wing throughout his second-half cameo, and when his shot was parried on 76 minutes the rebound granted Messi an incredible sixth treble of the season.
The free-scoring forward almost returned the favour for Tello with eight minutes remaining, but the youngster leant back and his placed finish narrowly missed the top corner.
And Messi issued another directive as to how it is done soon after, put through by Sergio Busquets before casually chipping the outrushing Alves for his – and Barcelona’s – fourth.
Moments following 4-1, Xavi came on for Iniesta to continue his rehab from injury and helped himself to a goal in the process, matching the Argentine’s lob for technique in preying on a defensive lapse.