Ernesto Valverde's side are six points clear of second-placed Atletico Madrid in the table after 16 rounds of matches, with Real provisionally 11 back in fourth - albeit with a game in hand following their participation in the Club World Cup.
Victory for the Blaugrana, who are unbeaten in all competitions since the sides' Supercopa de Espana series in August, would leave Madrid with a mountain to climb in the second half of the season to retain their title.
Here, Goal takes a look at everything you need to know ahead of the clash in La Liga on Saturday.
Ousame Dembele is still sidelined for Barcelona. The French winger had hoped to be back for the Clasico, but will instead target a return in January after stepping up his training in recent weeks.
Defender Samuel Umtiti and striker Paco Alcacer are also out, along with Gerard Deulofeu, while Rafinha is available again but has been excluded from the squad for the trip to Madrid.
Sergio Busquets has been booked four times in La Liga this season and was rested in the 4-0 win over Deportivo La Coruna last weekend to avoid the risk of a yellow card that would have seen him suspended for the Clasico.
Valverde has no players banned for the game in Madrid.
BARCELONA POTENTIAL STARTING LINE-UP
Busquets will return in midfield for Barcelona after he was rested for the win over Deportivo last weekend to avoid the risk of suspension for the Clasico.
Paulinho, who scored twice in that match, is set to continue in midfield along with Ivan Rakitic and Andres Iniesta, with Lionel Messi and Luis Suarez further forward.
The continued absence of Umtiti means another start for Thomas Vermaelen in the back, although Javier Mascherano is another alternative for what is likely to be his very last game as a Barca player before moving on in the January window.
REAL MADRID TEAM NEWS
Cristiano Ronaldo has been absent from training for Real Madrid for much of this week, but the Portuguese forward has been declared fit and will start the Clasico.
Gareth Bale is also in line for a start alongside Ronaldo and Karim Benzema for the very first time this season and Zinedine Zidane's side have no major injury worries heading into this Clasico clash.
Madrid beat Gremio to win the Club World Cup last Saturday and have finished 2017 with a club-record five trophies.
TV COVERAGE & KICK-OFF TIME
Real Madrid versus Barcelona kicks off at 13:00 local time at the Santiago Bernabeu on Saturday and will be broadcast live in the UK on Sky Sports Football and also on Sky Sports Mix from 11:30 GMT.
In the United States, Real Madrid v Barcelona can be watched live and on-demand with fuboTV with a seven-day free trial and kicks off at 07:00 ET.
BEST OPTA MATCH FACTS
This will be the 237th El Clasico in all competitions between Real Madrid and Barcelona. Los Blancos have won 95 and the Blaugrana 92, while there have been 49 draws.
Real Madrid, on 399, can become the first to reach 400 goals in the fixture. Barca currently have 384.
Zinedine Zidane's side won the last two Clasico clashes, both in the 2017 Spanish Supercopa (3-1 at Camp Nou and 2-0 at the Santiago Bernabeu). The last time Real Madrid won three consecutive matches against Barcelona in all competitions came back in 1978.
Barcelona have the chance to win three consecutive La Liga matches against Real Madrid at the Santiago Bernabeu for the first time in the club's history.
Cristiano Ronaldo has scored 17 goals against Barcelona in all competitions since he joined Real Madrid and could equal Alfredo Di Stefano as the all-time top Real Madrid scorer in El Clasico history (18).
Lionel Messi is the all-time top scorer in El Clasico history in all competitions (24 goals), the all-time La Liga top scorer in El Clasico history (16) and the all-time top scorer in El Clasico history at the Bernabeu (14).