Las Palmas are the visitors as Barca seek to stretch their perfect record in La Liga and Champions League this season to nine games.
However, the action on the field will play second fiddle with pro-secessionist politicians forging ahead with a planned referendum on independence for the wealthy north-eastern region of Spain despite the best attempts of the Spanish government, who have declared the vote illegal.
Outspoken central defender Gerard Pique called on people to vote peacefully with tensions heightened by a crackdown on those responsible for calling and organising the logistics for the vote to take place.
"Don't give them any excuse. It is what they want. And we will sing loud and clear. #Wewillvote."
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Barca have long supported Catalonia's right for a vote on independence, without throwing their weight behind the yes or no camp.
"It will be an important day in the history of our country, but we have to focus on football," said Barca vice- president Jordi Cardoner on Wednesday.
Among a number of measures being taken to impede the referendum, 14 regional government officials were detained last week.
Chants in support of independence are common at the Camp Nou in the 17th minute of each match to mark the fall of Catalonia in the Spanish War of Succession in 1714.
"I think that all members, fans and supporters will express what they think is right," added Cardoner on the likelihood of more pro-independence chants.
Las Palmas will aim to puncture the atmosphere under new management, as former Valencia coach Pako Ayestaran takes charge for the first time following Manolo Marquez's resignation after just six games in charge on Tuesday.
However, the European champions looked back to their best as they beat Borussia Dormund 3-1 on Tuesday in Champions League duty thanks in large part to Gareth Bale's return to form.
The Welshman scored a brilliant opener before teeing up the first of a double for Cristiano Ronaldo.
"He hasn't had it easy and I'm delighted for him," said Madrid boss Zinedine Zidane on Bale's display.
"Getting a goal like that is fantastic for him. This game will have done wonders for him and if you give him the space he's lethal."
Marcelo, Karim Benzema and Mateo Kovacic do remain sidelined by injury though. Elsewhere, second-placed Atletico Madrid can close to within a point of Barca with victory at Leganes on Saturday as they look to bounce back from their first defeat of the season at home to Chelsea on Wednesday.