Demonstrators condemned Rome's criticism of the Global Sumud Flotilla that sailed to challenge Israel's blockade of Gaza, where the United Nations has reported famine conditions after nearly two years of war.
Many also demanded more from Meloni, who has faced criticism for not speaking out more strongly on the situation in Gaza or recognising the State of Palestine.
The CGIL, one of two unions to call the strike, said over two million people across Italy had taken to the streets in over 100 demonstrations.
CGIL head Maurizio Landini noted "the extraordinary and unprecedented participation of young people, who are calling for a future of peace".
Up and down the country, from Turin and Trento in the north to Bari and Palermo in the south, people gathered for marches and flashmobs, blocking highways or train tracks.
The strike saw trains cancelled or delayed, some schools closed, and even some prisoners downing tools.
At least 80,000 people marched in Rome according to police. Organisers put the number at 300,000.
'Stop the War'
Among them was Giordano Fioramonti, 19, protesting along with other youngsters, university students, and professors.
"It's also our civic duty to show how angry and unhappy we are with what is happening in the world, with our government, to show our support for the flotilla, especially for Palestine, for the Gazans who are being killed, tortured and massacred," Fioramonti told AFP.
Over 80,000 people demonstrated in Milan, police told AFP, with a sea of people clapping and waving the Palestinian flag as they made their way through the streets, carrying a massive banner reading: "Free Palestine, Stop the War Machine."
Police set off smoke bombs to stop several hundred protesters who had broken off from the main march to occupy a ring road in Milan, television images showed.
Organisers said 50,000 people were marching in Turin and 40,000 in Genoa, while 10,000 protesters were blocking the port of Naples.
Commercial traffic was blocked at the port of Livorno, local media reported, and images in Bologna showed protesters marching down a section of the motorway that circles the city, a key artery between the country's south and the northeast.
Protesters in Pisa broke into the runway area of the airport and forced its closure for a short period, delaying some flights.
Meloni brands flotilla 'dangerous'
Italy's foreign ministry announced that Israel had released four Italian parliamentarians out of the 40 Italians detained from the flotilla.
The two members of parliament and two members of the European Parliament were due to arrive back in Rome on Friday, the ministry said.
"The flotilla was trying to do what European governments and the European Union should be doing, namely breaking this blockade of humanitarian aid that is causing a real famine in Gaza," said Elly Schlein, head of the Democratic Party (PD), the main opposition party.
"We call for a total arms embargo, as voted for by Spain. We call for full recognition of the State of Palestine," she told AFP.
READ ALSO: Meloni urges Gaza aid flotilla to stop as 40 Italians held
Meloni had called the flotilla a "dangerous, irresponsible" initiative, even though Italy sent a navy frigate to provide assistance.
She condemned the national strike, in comments at an EU meeting in Copenhagen Thursday, adding that "long weekends and revolution do not go together".
Meloni's reluctance to overtly criticise Israel and her unwillingness to break ranks with US President Donald Trump have spurred a wave of protests in recent weeks.
"You say you are a Christian Italian mother, but you should know that your policies towards Israel offend Christians, mothers, and all Italians who do not feel represented," said one protester in Rome on Friday, Giuliano Ferrucci, 60.
Italy's strike watchdog has called Friday's action illegal on the grounds that unions did not give the required 10 days' notice.
It "is not just any strike, it has a huge emotional impact and must be handled with care," the head of the Strike Guarantee Commission, Paola Bellocchi, told Corriere della Sera daily.
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