The Blaugrana can open up a six-point lead over their old rivals with a win on Saturday, when Gerardo Martino, Carlo Ancelotti and several players will make their Clasico debuts.
The Catalan giant last won a league fixture against Real Madrid in December 2011, as the club came from behind to win 3-1 in the Spanish capital.
Although Copa del Rey and Supercopa wins have since followed, Barca will be determined to end a run that has seen the club take just one point from its last three league meetings with Madrid.
Gerardo Martino's table-topping team is the only side to avoid defeat in La Liga this term, having recorded eight wins and one draw.
The club was held to a goalless stalemate at Osasuna last week and drew with AC Milan in Italy in midweek, but will hope a return to Camp Nou - where the team has won its last 19 Liga matches - helps it return to winning ways.
Real Madrid sits third in La Liga, three points adrift of Barca, with the club's only loss of the season coming against Atletico Madrid at the end of September.
Both sides have new stars keen to make an impact in their first Clasico - Neymar in Barca's case, and Gareth Bale, Isco and Asier Illarramendi for Madrid - while coaches Martino and Carlo Ancelotti will also experience their first taste of Spain's fiercest derby.
While much attention will focus on the impact of Neymar and Bale - the latter having returned from a back injury against Malaga on Saturday - Cristiano Ronaldo and Lionel Messi are more than likely to steal the show.
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 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.
Madrid will be without midfielder Xabi Alonso, despite him returning to training following a broken foot, while Barcelona defender Jordi Alba (hamstring) will also miss the fixture.
Historically, Real Madrid has shaded the clash, winning 90 of the 224 competitive matches, with Barcelona winning 86.