Ernesto Valverde's side endured a tough pre-season in which they lost the Spanish Super Cup to Los Blancos and saw Neymar leave the Nou Camp to sign for Paris Saint-Germain.
However, Luis Enrique's replacement has managed to put the Catalans back on the right track with a line-up low on talent but bathed in fortitude and steel.
Barcelona indeed lead La Liga comfortably with 42 points in 16 matches, having conceded only seven goals in the process.
The Catalans are 11 points ahead of Real in the table and although Los Blancos have a game in hand, a Blaugrana victory in El Clasico will all-but secure the title ahead of the winter break.
Atletico Madrid and Valencia have emerged as potential contenders, with Los Colchoneros only six points behind Barcelona and two ahead of Los Che.
The first El Clasico of the La Liga season could be decisive for the title and Valverde is expected to deploy a strong eleven, only hindered by the absence of Umtiti in defence.
Thomas Vermaelen to replace Umtiti
The France international centre-back was one of Barcelona's best players during the opening part of the season and would have started alongside Gerard Pique against Real has he been fit.
Valverde has two options to cover his absence in Thomas Vermaelen and Javier Mascherano but the former has emerged as the surprising favourite to start at the Santiago Bernabeu. The ex-Arsenal defender has impressed in recent games while Mascherano has been out of action since suffering a hamstring injury on international duty with Argentina on 14 November.
The veteran defender is fully fit again but might not be in the right mental state to play amid reports claiming that he will join Chinese club Hebei China Fortune once the transfer window re-opens in January.
Sergi Roberto or Nelson Semedo at the right-back
Semedo was brought from Benfica in summer to fill the huge gap left by Dani Alves from the previous summer. However, the versatile Sergi remains Valverde's favourite to cover the right-back position.
Semedo has only started seven league games and his defensive strength was compromised during a disappointing performance in the recent 1-1 draw against Valencia.
Sergio Busquets will resume his place in the middle of the park after being rested for the 4-0 victory against Deportivo la Coruña while Andres Iniesta and Ivan Rakitic should be in charge of dictating the game.
Paulinho to partner Messi and Luiz Suarez
Valverde has tried different combinations in attack since Neymar's departure to Paris Saint-Germain. Ousmane Dembele was destined to be the Brazilian's replacement but the long-term injury he sustained forced Valverde to rethink his plans.
Gerard Deulofeu, Aleix Vidal, Denis Suarez have been among the options used by the Barcelona boss to accompany Messi and Suarez during the opening part of the season. Paco Alcacer was the chosen one in the last win over Deportivo but he was forced off in the first-half with an injury which will see miss the trip to Real.
So Paulinho has emerged as the main candidate to perform as the anchor between the midfield and the attack after having enjoyed an impressive start to the life at the Nou Camp. The Brazilian has scored six league goals, netting a brace in the win over Deportivo and everything indicates that he will again be named in the starting line-up to add some strength to Barcelona's midfield against Real.
Dembele and Rafinha
Neither Dembele or Rafinha will start the game but there is still a question mark over whether either of Barcelona's long-term absentees will have a chance to make the bench to play a part in the second half.
On Monday [18 December] Barcelona said that the Brazilian had received medical clearance to return to action but Valverde recenty suggested that he won't risk him or Dembele unless they are 100% fit.
Umtiti, Paco Alcacer and Arda Turan are ruled out due to different fitness problems while Deulofeu remains a doubt, having only returned to training on Thursday [21 December] from another muscle injury.