The six-time Ballon d'Or winner's first appearance in the Clasico cauldron came back in 2005 and he has been lighting up games ever since.
Given their volume, it is difficult to choose which of his Clasico games are the most memorable, but Goal takes a look at the games where Messi was king...
#10 Real Madrid 0-3 Barcelona, December 2017
Messi scored from the penalty spot to put Barca 2-0 up in the capital before providing a clever cut-back cross for Aleix Vidal to make the final score 3-0.
It was a comparatively subdued performance from the Argentine, but he still had a hand in two goals.
#9 Real Madrid 2-1 Barcelona, August 2012
Despite losing the 2012-13 Spanish Supercopa to Real Madrid, Messi nevertheless was on form, contributing goals in both legs of the decider.
Barca won the first leg 3-2, with Messi scoring from the penalty spot, but they were undone in the second leg at the Santiago Bernabeu.
However, the second leg saw Messi's most memorable contribution in the form of a free kick, which he curled into the left corner to give Barca hope.
Unfortunately for Messi and Co. though the game ended 2-1 and Real won thanks to the away goals rule.
#8 Barcelona 2-2 Real Madrid, October 2012
Messi scored both of Barca's goals - the first being a predatory follow-up finish inside the box and the second from a set-piece, which left Iker Casillas grasping desperately at air.
The game was something of a symbolic stand-off between Messi and Cristiano Ronaldo, who scored Real's two goals.
#7 Real Madrid 3-4 Barcelona, March 2014
The 2013-14 season wasn't particularly special for Barcelona, whose only silverware that season came in the form of the Spanish Supercopa, or Messi, whose goal tally dipped significantly by his high standards.
However, one of the season's high points was undoubtedly Messi's virtuoso display in El Clasico at the Santiago Bernabeu, where he scored a hat-trick and set up Andres Iniesta in a 4-3 victory.
The Argentine showed ice-cool composure to score the winning goal from the penalty spot with just over five minutes left on the clock.
Barca finished the season runners-up in La Liga behind Atletico Madrid and they secured second place ahead of Real Madrid on goal difference thanks to a single goal - meaning their Clasico triumph was ultimately crucial.
#6 Real Madrid 2-6 Barcelona, May 2009
Their Clasico win over Real Madrid at the Santiago Bernabeu in that campaign may be considered by some to be as good as a trophy considering its emphatic nature and Messi was orchestrating things.
The Argentine set up Thierry Henry for his side's first, then scored their third and fifth goals on the way to one of their biggest wins over the capital club.
#5 Barcelona 3-2 Real Madrid, August 2011
Messi kicked off the 2011-12 season in sensational fashion with two virtuoso displays in the Spanish Supercopa, in which he was directly involved in all five of Barca's goals across the two legs.
Having set up and scored in the first leg at the Santiago Bernabeu, the forward took things up a gear in the second leg at Camp Nou, stepping up in the final minutes of the tie to score the winner - his third goal over the two matches.
#4 Real Madrid 0-3 Barcelona, November 2005
The year 2005 saw Messi's first taste of El Clasico and he relished the opportunity, showing little fear by driving at opponents such as Roberto Carlos, Zinedine Zidane and Sergio Ramos.
He was unlucky not to score at the Santiago Bernabeu, having carved out a number of chances, but he did claim an assist for Samuel Eto'o, who stole the ball from the weaving Argentine and bagged Barca's first in a dominant 3-0 win.
Messi lasted 70 minutes before being replaced by another upstart in Andres Iniesta, but 70 minutes was sufficient to convince the Barca faithful that they had a generational talent on their hands.
#3 Real Madrid 0-2 Barcelona, April 2011
The first leg was played at the Santiago Bernabeu and Messi dictated proceedings from the beginning, ultimately scoring the only two goals in a Barcelona victory.
While his first was a classic striker's finish, meeting a driven cross at the front post, his second goal in the 2-0 win was a truly mesmeric solo effort.
Just inside the Real Madrid half, Messi gave the ball to Sergio Busquets, who more or less got out of the onrushing Argentine's way as he slalomed through the attentions of four players before slotting past Iker Casillas.
#2 Barcelona 3-3 Real Madrid, March 2007
Messi was still only a teenager when he scored his first goals against Real Madrid back in 2006-07.
Strutting the Camp Nou stage with the likes of Ronaldinho, Samuel Eto'o and Deco, the then-19-year-old announced his arrival to El Clasico with a debut hat-trick, outshining his elders with some polished finishing.
All three of Messi's goals were equalisers in a game which finished 3-3. Real Madrid twice took the lead through Ruud van Nistelrooy twice and then Sergio Ramos, but, in what would soon become a recurring theme at Barca and elsewhere, Messi was on hand to save the day.
#1 Real Madrid 2-3 Barcelona, April 2017
El Clasico has an edge to it before a ball is even kicked thanks to the weeks of build-up, not to mention the bitter history between the clubs, and Messi contributed to the saga magnificently in 2017.
The Argentine scored two goals in a 3-2 win and it was his second which will echo through the ages. With game tied at 2-2 and the clock ticking into added time, Messi got onto the end of a Jordi Alba pass, placing the ball beyond Keylor Navas to cap a wonderful counter-attack.
It was his 500th goal for Barcelona, but the best was yet to come.
Wheeling away in celebration, Messi then rubbed salt directly into the wound by taking off his jersey and holding it out in front of Real Madrid fans - a taunt that would later be copied by Cristiano Ronaldo.