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 giants showed no signs of residual damage from their first Liga defeat of the season at the hands of Real Sociedad last weekend, completely dominating the visitors, who played the majority of the match with ten 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 signalled the end of Osasuna's challenge, and allowed the Argentine to strike again from the penalty spot.
Shortly before half time, Pedro added the Blaugrana's third despite suspicions of offside, but luck was never on the visitors' side, and a quickfire double from Messi minutes after the restart completed their miserable outing.
Barca reopen their 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.
The Catalan giants were 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.
However, the visitors were 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 hosts’ 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 half time, but after doing so well to steal ahead of Bertran at the near post, he could only direct his finish onto the woodwork.
But Barca would get their 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.
And before Osasuna had even caught their breath, Barca had their 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 their lead. Substitute Alexis Sanchez dragged a swivel shot just wide, before Villa blasted over the bar and was thwarted by Fernandez at the death.
But 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 them.