Protesters against Europe's austerity policies, estimated by police at 1,500 but by Blockupy at 3,000, descended in the early hours on Frankfurt's financial district to disrupt business at institutions they blame for a deep recession in euro zone countries such as Spain and Greece.
Riot police, showered with stones and paint bombs, used pepper spray to prevent the protesters breaking into the ECB. Several protesters were injured and police made some arrests, though they gave no numbers.
"The aim of this blockade is to prevent normal operations at the ECB," said Blockupy spokesman Martin Sommer, adding that some people who had tried to come to work had been sent home by the protesters.
Demonstrators brandished signs with slogans such as "Humanity before profit" and some held up inflatable mattresses with the slogan "War Starts Here" written on them.
Trucks with water cannons stood by and a helicopter hovered overheard.
Europe's Blockupy movement was formed after the Occupy Wall Street movement in 2011.
One of the protesters, Lena Turowski, a 25-year-old student of international development, condemned European governments' embrace of austerity measures to repair their economies.
"At the moment, they are trying to fight the crisis with the same measures that caused the crisis. And the people are being forgotten about," she told Reuters.
"It is also about solidarity with those who are being affected by austerity and crises in their countries," she said.
Friday's protests, a prelude to Europe-wide rallies planned for June 1, coincided with fresh data from the EU statistics agency Eurostat showing that euro zone unemployment reached a new high of 12.2 percent in April.
Governments struggling with large debt burdens have cut spending and raised taxes, contributing to widespread recession across the euro zone, while many families are deep in debt or have lost their homes after property bubbles burst.
Germany's own economy has, however, been fairly resilient to the crisis.
As the day progressed, hundreds of the protesters spread out to Frankfurt's airport and to the city's main shopping strip, where they stormed into fashion stores and blocked entrances, keeping shoppers out.
Police used batons to keep the protesters out of the main air terminal and only allowed people with flight tickets inside.
A spokesman for airport operator Fraport said air traffic was not affected by the protest.
Many of Frankfurt's financial institutions urged staff to take Friday off following a state holiday on Thursday.
"We have skeleton staffing here again and we are dressed in jeans and t-shirts so no one will take notice of us," said one trader at Frankfurt's stock exchange.
The ECB said it had taken measures to remain operational and to ensure the safety of its staff.
At a similar anti-capitalist demonstration about a year ago in Frankfurt, police detained hundreds of people for defying a temporary ban on the protests.
Friday's protests went ahead after a court granted last-minute permission, brushing aside complaints from Fraport and from the city of Frankfurt, though its ruling limited the number of protesters to just 200.