The referendum, scheduled for October 1, and which the Spanish Constitutional Court has declared to be illegal.
Spanish Prime Minister Mariano Rajoy called for "a return to normality and a return to common sense".
Police confiscated almost 10 million ballot papers, the Interior Ministry said.
Authorities seized almost 10 million ballots destined for the vote, seriously damaging separatist plans for a referendum with a semblance of legitimacy, even if it was never going to be recognised by Madrid or overseas as it violates the constitution. Madrid also tightened the finances of the restive region in hopes of dissuading Catalans for going ahead with referendum.
It was the police's first raid of government offices in the region.
Spain's central government braced for a second day of protests in Barcelona yesterday as separatists called for "permanent mobilization" after Madrid dealt yet another blow to preparations for an outlawed referendum on independence.
Catalonia has about 5.5 million eligible voters.
Some 7.5 million people live in Spain's well-off north-eastern region and a majority are thought to be in favour of having a vote.
At least 12 Catalan officials, including the Junior Economic Minister, were captured in the course of the raids.
Altercations broke out in Barcelona and other Catalan cities on the eve of the arrests.More news: Emmys 2017: What got bleeped out from Elisabeth Moss' acceptance speech
"The referendum will be held and is already organized", Mr. Romeva said. It gave no details on the number of agents involved.
The Spanish government has said the referendum won't happen, but on October 1, many Catalans are likely to try to vote, or at least take to the streets to have their voices heard.
A leading editor has said the Spanish and Catalan governments are headed for a major clash as the ongoing row of independence grows.
The central government has also taken over the payment of essential services and public workers' salaries in Catalonia to prevent the money from being spent on the referendum. The decision came after Catalan officials failed to voluntarily agree to the controls.
Catalan separatists have retorted that they have a democratic right to decide on their future. Spain's government has been backed by the Constitutional Court, which has suspended the referendum law passed by the Catalan parliament.
"We're no longer discussing whether Catalonia has independence".
Here are the key dates in the wealthy Spanish region's independence drive.
"Spanish Guardia Civil officers raided a dozen Catalan regional government offices and arrested 14 senior officials on Wednesday as part of an operation to stop the referendum from taking place", The Guardian says.
Catalonia's vice-president admitted on Thursday that plans to hold an outlawed independence referendum had been dealt a major blow by a crackdown the previous day, as people gathered in Barcelona for a second day of protests.
Quebec and the Catalan government signed a co-operation agreement in 1996 that extends into many areas including culture and education.
He added: "This is a judicial operation which is being done to guarantee ... that the law is respected".