Chanting "Independence" and "Free political prisoners", several thousand Catalan protesters gathered near Barcelona's Nou Camp stadium on Wednesday hours before the re-fixed game against Real Madrid.
Despite a heavy police presence, some of them blocked a major avenue near the stadium, disrupting traffic.
Known as "El Clasico," the match had initially been scheduled to occur two months ago. However, it was postponed on security concerns due to unrest in the wealthy northeastern region after Spain's Supreme Court in October sentenced nine Catalan separatist leaders to up to 13 years in prison.
Wednesday's protest was called by secretive Catalan protest group Democratic Tsunami, which says it favours peaceful civic disobedience and whose main goals are to get Spain to negotiate on Catalonia's right to self-determination and to achieve freedom for the jailed separatists.
Many protesters carried banners that read "Spain, sit and talk" and the organisation said on Twitter it would distribute 100,000 of those banners to the people attending the game. It also told them to bring inflatable balls and to write on them a "message for the world".
Democratic Tsunami, which organised mass protests at Barcelona's airport in October and blocked a major highway, said it does not wish to blockade or suspend the match.
Authorities have assembled a 3,000-strong force of public and private security officers to guarantee the match will not be disrupted, but declined to say how that compared to other "El Clasico" games.
The Spanish central government has sent around 500 additional anti-riot police to Barcelona, who would only intervene if the Catalan police asks for their help, said a national police spokesman.
Protesting in front of a hotel near the stadium where both teams were resting, pro-independence voter Marta Canaves, 53, said that the venue was a "great place to make visible to the rest of the world" the situation in Catalonia.
"We want to be heard and to vote," added her friend Emma Castells, 55, referring to separatist demands to hold a referendum on independence.