The Argentine stepped above and beyond his usual brilliance, plundering two goals in either half to get the Blaugrana back to winning ways in the league.
The Catalan giant showed no signs of residual damage from its first Liga defeat of the season at the hands of Real Sociedad last weekend, completely dominating the visiting side, which played the majority of the match with 10 men.
Messi got the ball rolling with his first 11 minutes in, and despite Raoul Loe briefly restoring parity, Alejandro Arribas' red card for handball just before the half hour mark signaled the end of Osasuna's challenge and allowed the Argentine to strike again from the penalty spot.
Shortly before halftime, Pedro added the Blaugrana's third despite suspicions of offside, but luck was never on the visitor's side, and a quickfire double from Messi minutes after the restart completed the miserable outing.
Barca reopens the 11 point gap over second-placed Atletico Madrid, though that advantage could be reduced to eight points should the capital outfit triumph at Athletic Bilbao later on Sunday.
David Villa, Carles Puyol and Thiago Alcantara were all handed starts by Jordi Roura, who elected to rotate his squad, with the likes of Andres Iniesta and Jordi Alba on the bench.
Barca was gifted the lead after only 11 minutes, when a dreadful clearance from Andres Fernandez was punished by Messi, who danced around the Osasuna keeper before slotting home, after excellent work by Xavi to pounce on the loose ball.
Osasuna was back in the game with 24 minutes on the clock. Barca failed to properly clear, and Marc Bertran’s cross ricocheted to the edge of the area, where Loe was waiting to drill precisely into the bottom left corner.
But Osasuna’s joy barely lasted three minutes, because Arribas’ handball inside the box earned him an early bath with his second yellow card and gave Messi the perfect opportunity to restore the host’s lead from the spot with a cool penalty that sent Fernandez the wrong way.
The Argentine could have completed his hat trick seven minutes before halftime, but after doing so well to steal ahead of Bertran at the near post, he could only direct his finish onto the woodwork.
Barca would get its third in controversial circumstances two minutes later. Xavi’s pass found Dani Alves at least a yard offside, but no flag was forthcoming, giving the Brazilian fullback the time he needed to pick out Pedro to score.
It was 4-1 shortly after the restart, as Villa did well to slip a clever pass between a defender to pick out Messi, who rounded Fernandez for the second time to slot home.
Before Osasuna had even caught its breath, Barca had a fifth. Adriano this time set events in motion with a devilish low cross into the area, where Messi ghosted ahead of his man to score for the fourth time.
The Catalans were on fire, and had further chances to extend the lead. Substitute Alexis Sanchez dragged a swivel shot just wide, before Villa blasted over the bar and was thwarted by Fernandez at the death.
Despite no more goals forthcoming, Barcelona finished the match in complete control, and wasted little time in putting last week's shock result at the Anoeta Stadium behind it.