La Liga: Barcelona 7 Osasuna 0
The Argentina international was already the club's leading goalscorer in official matches, but reached another milestone on Sunday as he surpassed Paulino Alcantara's mark of 369, which included goals in friendlies.
Barcelona's comfortable win represented the perfect tonic for head coach Gerardo Martino, who witnessed his side produce a masterclass in front of their home support.
The Argentinian has faced criticism after overseeing three defeats in the space of six league games, including a shock 1-0 reverse at relegation-threatened Real Valladolid last weekend.
Barca answered their critics in some style, however, with Alexis Sanchez, Andres Iniesta, Cristian Tello and Pedro also getting their names on the scoresheet, ensuring the Catalans will head into next weekend's Clasico with rivals Real Madrid in confident mood.
After Messi had opened the scoring to move level with Alcantara's record, Alexis doubled the advantage from close range and Iniesta let fly with an unstoppable 25-yarder to make it 3-0 by half-time.
Alcantara's record was then surpassed by Messi's fierce strike from a tight angle shortly after the hour mark and substitute Tello added a fine individual goal before Messi struck again and laid on the seventh for Pedro.
The result leaves Barcelona third, four points adrift of Liga leaders Real ahead of their crucial meeting, while Osasuna stay 15th, just three points clear of the drop zone.
Osasuna started in a positive manner and the hosts were handed a huge reprieve in the 10th minute.
Emiliano Armenteros' initial effort was parried by Victor Valdes and Oriol Riera tapped home the rebound, only for his celebrations to be curtailed by the linesman's offside flag.
Osasuna remained keen to take the game to Barca, but were punished by a fine move from the hosts after 18 minutes.
Xavi's pass into the area released Alexis, who cut the ball back from the byline for Messi to side-foot home.
That goal settled the home side and within four minutes the early cobwebs had been completely brushed off as Alexis gained reward for his lively opening with a goal.
Jordi Alba played a neat one-two with Iniesta before the full-back delivered a teasing ball across goal, with Alexis on hand to apply the finishing touch.
The game was essentially put beyond doubt on 34 minutes when Iniesta unleashed a left-footed effort past Andres Fernandez and into the top right-hand corner from 25 yards.
Barcelona picked up where they left off in the second half and grabbed a fourth after 63 minutes.
Iniesta cleverly worked his way into the area before laying the ball to Messi, who fired across the goalkeeper from the left edge of the six-yard box.
Tello replaced Alexis in the 76th minute and wasted little time in making it 5-0, rounding off a fine run with a curling strike into the far corner.
Messi completed his hat-trick with two minutes of normal time remaining after Daniel Alves had controlled a long ball superbly before passing across the area.
Yet there was still time for another goal as Messi found Pedro, who drilled home to complete the thrashing.