"We came here to demand a political dialogue in connection with the situation in Catalonia", one of the protesters said before the game.
Many protesters were carrying banners in English that read: "Spain, sit and talk". The demonstrators sought to use the match between the two most famous Spanish football clubs, which was broadcast in many countries across the world, to draw attention to the Catalan independence issue.
Over 3,000 security forces have reportedly been dispatched to ensure order during the protest.
Once the match started, radical protesters began building barricades of garbage containers and road signs near the stadium, pelting police with various objects, including cans and bottles, according to the broadcast by Spain’s LaOtra television channel.
The police have responded with batons and rubber bullets.
The LaSexta TV channel, meanwhile, reported that law enforcement officers had fired tear gas. At least one person is said to have been detained in the unrest, which sparked after the football game was over.
Last week, Catalan pro-independence group Democratic Tsunami urged its supporters to gather near the Camp Nou stadium for a "massive" protest on 18 December. The match with Real Madrid was initially due to take place on 26 October but was delayed in light of mass unrest in the Catalan capital.