Italy has now registered more cases of coronavirus than any country outside China, while its death toll has risen to 366.
After mass testing uncovered more than 7,300 infections, the country has followed China's lead and has now locked down around 16 million people – more than a quarter of its population – for nearly a month.
Weddings, museums, cinemas, shopping centres and restaurants have all been hit by new restrictions.
Italian prime minister Giuseppe Conte signed a quarantine decree early on Sunday for the north of the country.
Areas under lockdown include Milan, Italy's financial hub and the main city in Lombardy, and Venice, the main city in the neighbouring Veneto region.
The extraordinary measures will be in place until April 3.
The fate of foreign visitors stuck in Italy's new quarantine zones is still unclear.
The Pope, who has been ill, held his Sunday blessing by video instead of in person.
He described feeling like he was "in a cage."
The Vatican museums are now closed, including the Sistine Chapel.
Alitalia, the Italian airline which was already financially ailing before the virus, suspended all national and international flights from Milan's Malpensa airport, starting on Monday.
The World Health Organisation has said China's move to quarantine about 60 million people in central Hubei province in late January has helped the rest of the world prepare for the virus to arrive.
WHO chief Tedros Adhanom Ghebreyesus tweeted his support Sunday for Italians and their "bold, courageous steps aimed at slowing the speed of the coronavirus".
China has suffered about three-fourths of the world's 109,000 coronavirus infections and most of its nearly 3,800 deaths.
But new infections in China have levelled off dramatically and most of those infected, in China and globally, have already recovered.
In waters around the world, the virus outbreak has left the cruise ship industry in disarray.
The Grand Princess cruise ship, on which 21 people have tested positive for the virus, was heading Sunday to Oakland after idling off San Francisco for days. It expects to stop there on Monday.
Americans will be transferred to facilities around the country for testing and isolation but it is not yet clear what will happen to passengers from other countries.
The ship had a cluster of almost 20 infections during an earlier voyage that has led to one death.
Another cruise ship is in quarantine on the Nile in Egypt, with 45 confirmed virus cases.
Two other ships with no confirmed cases were turned away this weekend from Malaysia and Malta amid virus fears.
The US death toll from the virus climbed to 19, with most victims in Washington state.
Infections rose to more than 430, including the first case in the nation's capital.
Even as the virus spreads, dozens of research groups around the world are racing to create a vaccine.
As of Saturday, nearly 90,000 cases have been reported in Asia; more than 10,000 in Europe; about 7,000 in the Middle East; around 450 in North America, Latin America and the Caribbean, and fewer than 50 cases reported so far in Africa.
More than 60,000 people have recovered worldwide.
China reported 44 new cases over the past 24 hours, the lowest level since it began publishing nationwide figures on January 20, and 27 new fatalities.
Italy is now the No. 2 epicentre, surpassing South Korea, whose total is now 7,313, with 50 deaths overall.