Javier Mascherano, André Gomes, Sergi Roberto, Arda Turan, Ousmane Dembele and Rafinha Alcantara will all be unavailable when Barcelona visit Leganes on Saturday (18 November) due to varying injuries.
However, Ernesto Valverde will welcome back Aleix Vidal into his 18-man squad to travel to Madrid after the former Sevilla wing-back missed the last four games due to an ankle injury.
Mascherano is set to be on the sidelines for around four weeks after suffering a hamstring injury on international duty with Argentina.
The defender is expected to miss the next seven or eight games and may not return to action until the first El Clasico in La Liga at Real Madrid on 23 December.
The situation has left Valverde with a big selection dilemma as the trip to Leganes will come just before two crucial away games against Juventus in the Champions League (22 November) and Valencia in La Liga (26 November).
Gerard Pique and Samuel Umtiti are available but the two regulars starters are only one yellow card away from suspension and will so miss the visit to the La Liga second-placed Valencia if they are booked on Saturday [18 November].
Valverde refused to reveal his plans during the press conference ahead of the game but the Barcelona boss may be forced to hand Thomas Vermaelen his first La Liga appearance of the season against Leganes in order to rest either Pique or Umtiti for Valencia.
"We have good centre backs, you can never predict what's going to happen and there are always injuries when you least expect it," Valverde said when asked about it in the press conference ahead of the game.
"This Saturday we will put out our best team. We will take into account it is a week with difficult opponents, the first of which is Leganes."
The trip to the Real Madrid's neighbours will also come too early for Gomes and Roberto after the two midfielders missed the 2-1 win over Sevilla prior the international break due to respective muscle injuries.
Meanwhile, Turan was expected to be available to face Leganes after Barcelona revealed that the Turkey international was back in training.
However, the club has listed the former Atletico Madrid playmaker among the players who will miss the clash with Leganes amid speculation linking him with a January move away from the Nou Camp.
Long-term injury duo Dembele and Rafinha also remain on the sidelines but Vidal is back after having recovered from an ankle injury.
The versatile wing-back has missed the last four games after feeling some pain in the ankle which last season saw him missing more than five months following surgery.
However, the 28-year-old full-back has taken advantage of the international break to step up the recovery and will be available to face Leganes if called upon by Valverde.
Elsewhere, Luis Suarez has also been included in Valverde's squad with the Uruguay international having undertaken a special training programme during the break to put his knee woes behind him.
Yet, the striker had been playing with a niggle in his knee since suffering an injury earlier in the season during the Catalans' 2-0 defeat to Real in the second leg of the Spanish Super Cup on 16 August.
Valverde will be hoping Suarez can recapture his best form in the coming games in order to help his side consolidate their leadership at the top of the La Liga table, with Barcelona four points ahead of Valencia and eight over Real Madrid and Atletico Madrid after 11 games.
Barcelona 18 man squad to face Leganes:
Ter Stegen, Cillessen, Semedo, Piqué, Rakitic, Sergio, Denis Suárez, Iniesta, Suárez, Messi, Paulinho, Deulofeu, Paco Alcácer, Jordi Alba, Digne, Aleix Vidal (who has received medical discharge), Umtiti and Vermaelen.
It should be noted that Gerard Piqué won't travel with the team because of a personal matter. He will join the group in Madrid early on Saturday. In addition, Dembélé, Rafinha, Arda Turan, Sergi Roberto, André Gomes and Javier Mascherano remain on the injury list.