Violent clashes between protesters and riot police broke out outside the Camp Nou stadium as Barcelona took on Real Madrid.
Authorities sought to keep Catalonia's separatist movement from disrupting the fixture, with thousands of officers and guards deployed in and around the stadium.
But riot police were forced to use batons to keep the crowd back as violence unfolded. Demonstrators threw objects at officers lined up behind shields and other protesters fought among themselves.
At least 12 people were injured and two were arrested following the clashes in Barcelona on Wednesday night, it was reported.
Plastic bins were set on fire, and the smell of smoke wafted into the Camp Nou and when the the game ended, fans were directed to leave on the stadium's south side to avoid the clashes outside.
The separatists sought to promote their independence bid by using the media coverage of the game between Barcelona, the Spanish league leaders, and its fierce rival Real Madrid.
Known as El Clasico, the game was postponed from October 26 amid violent protests by the separatists.
As crowds entered Europe's largest football stadium, security guards confiscated masks of Barcelona's Argentine star Lionel Messi from supporters, apparently to ensure they could be identified on closed-circuit cameras if they broke the law.
And as the game – which ended goalless - began, some fans held up blue signs saying "Spain, Sit and Talk" and "Freedom".
Others chanted, in Catalan, "Freedom for the Political Prisoners". Those messages referred to the Spanish government's refusal to discuss the wealthy north-eastern region's independence, as well as the recent imprisonment of nine of the movement's leaders convicted for their roles in a failed 2017 secession bid.
Fans also threw beach balls onto the pitch and raised banners with the message “Spain, sit and talk”
Protest organisers said over 25,000 people signed up to demonstrate near the stadium in Barcelona, Catalonia's capital, although it was hard to distinguish between protesters and fans.
There was a festive atmosphere before the game, though some protesters briefly blocked main roads to the stadium.
