At least 91 people were confirmed injured in clashes out of more than 330 who went to hospital, emergency services said, as police cracked down on what the Spanish central government branded a "farce".
The violence further heightened tensions between Madrid and the authorities in Catalonia in the worst political crisis the country has witnessed in decades.
"Spanish democracy faces its greatest challenge," headlined top-selling El Pais daily just hours before police moved in en masse to seal off polling stations and seize ballot boxes, sparking scuffles as they sought to block the vote.
In the second such vote in three years, more than 5.3 million people were called on to have their say on independence from Spain in the wealthy northeastern region which has its own distinct language and culture.
The referendum poses the question: "Do you want Catalonia to become an independent state in the form of a republic?"
- 'End this farce' -
But it has been ruled unconstitutional by the central government and the courts, with judicial officials ordering police to seize ballot papers, detain key organisers and shut down websites promoting the vote.