The Catalan giants last won a league fixture against Real Madrid in December 2011, as they came from behind to win 3-1 in the Spanish capital.
And although Copa del Rey and Spanish Super Cup wins have since followed, Barca will be determined to end a run that has seen them take just one point from their last three league meetings with Real.
Gerardo Martino's table-toppers are the only side to avoid defeat in La Liga this term, having recorded eight wins and one draw.
Both sides have new stars determined to make an impact in their first Clasico - Neymar in Barca's case, and Gareth Bale in Real's - while managers Martino and Carlo Ancelotti will also experience their first taste of Spain's fiercest derby.
"Even though players might never have participated in one, they understand the importance of a game between Barcelona and Real Madrid. A Clasico is the pinnacle for any player," he said.
Widely regarded as the two best players on the planet, both have made an outstanding start to the current campaign, with Ronaldo's brace in a 2-1 UEFA Champions League win over Juventus on Wednesday taking him to 15 goals from 12 appearances this season.
Four-time world player of the year Messi, meanwhile, has 12 goals in nine outings.
Real boss Ancelotti was happy with his side's win over the Serie A champions and hinted at Bale being involved from the start in Barcelona.
"We've now played three games with this formation (4-3-3). The team are comfortable with this system and we are not going to change it. Gareth Bale likes to play on the right and he will always play there," said the Italian.
"The team are confident. We now have to go to the Camp Nou to win, and we will need to be at our best - showing our best qualities."
