Second-half goals from Luis Suarez and Lionel Messi gave the Catalans' a 2-0 victory against 10-man Villarreal on Sunday (10 December) to consolidate their place at the top of La Liga table.
Barcelona are five points ahead of Valencia and six clear of Atletico Madrid, with Real Madrid surprisingly in fourth place, eight points behind after only 15 games.
However, the win at Villarreal may have come at a cost for the leaders with Busquets receiving his fourth yellow card of the season in the 45th minute of the game following a clear foul on Raba.
That deserved yellow card means that the Spain international will miss the highly-anticipated trip to Real on 23 December should he be booked again when Barcelona host Deportivo on Sunday.
Ernesto Valverde might rest him on Sunday to avoid that situation but, if not, Busquets will be hoping to stay out of trouble to be available for El Clasico.
Busquets' potential suspension for the visit to Real Madrid would give the Barcelona boss a major headache over who to select in midfield with Busquets having started 14 of the opening 15 La Liga games of the campaign.
Sergi Roberto, Ivan Rakitic, Andre Gomes, Paulinho or the versatile Javier Mascherano could all provide cover for the Spaniard in case of an emergency but Busquets is the only specialist in Valverde's ranks to play in the holding role.
Mascherano himself, Andres Iniesta, Ousmane Dembele, Rafinha Alcantara and Samuel Umtiti missed the win over Villarreal due to different injuries but the first two should be available for El Clasico in two weeks.
Meanwhile, Real won't play another La Liga game until the visit of Barcelona as the Champions League winners are currently in Abu Dhabi to play in the Fifa Club World Cup.
Zinedine Zidane's side will begin the defence of the title in a semi-final against Al Jazira on Wednesday with the final to be played three days later.
Real could therefore arrive back for El Clasico 11 points behind Barcelona but with one game in hand if the Catalans secure the three points against Deportivo.