The children defied calls from politicians to stay in school, instead leaving their classes at lunchtime on Thursday and making their way to the steps of Melbourne's Flinders Street Station to rally.
Chants calling for a free Palestine rung out as organisers encouraged the demonstrators to make their way onto the Flinders Street intersection, blocking cars and trams.
"We must demand Israel ends its genocide in Gaza," one speaker told the crowd.
"We demand the government cut all political, economic and military ties."
The crowd carrying placards calling for an end to the war then marched down Swanston Street and into Melbourne Central, where they staged a sit-in.
"We will never back down until Palestine is free," another speaker yelled.
Seba, 15, felt it was important to leave school early and rally in the city centre.
"No matter who you are - you don't deserve to die, you don't deserve to watch your family members die," she told AAP.
"I get education is important but it's not more important than people's lives."
Mazen, 16, had the backing of his parents and teachers to take the afternoon off to protest.
The school students gathered inside the Melbourne Central shopping centre and held a sit-in. (James Ross/AAP PHOTOS)
"It doesn't matter about school - there are people that are dying," he said.
The demonstration came after the Melbourne electorate office of federal minister Bill Shorten was splashed with red paint and graffiti reading "dial down the apartheid Bill".
Mr Shorten suspects the incident was in response to his plea for protesters to "dial down the degree of aggro", after bloodied replicas of corpses in Gaza were left outside the offices of federal politicians last week.
"Obviously someone took offence at me saying we should promote social cohesion and dial down the aggro in the confrontation," Mr Shorten told Melbourne radio station 3AW.
Speaking about the student strike, Mr Shorten said while he understood the merit of protests, the world needed more people with an education instead of missing school.
Federal ministers encouraged students to skip the rally and instead attend school. (James Ross/AAP PHOTOS)
Federal Education Minister Jason Clare echoed the sentiment.
"There is no make-ups or catch-ups or redoes," he told Nine's Today program.
"If students aren't in school then it will be considered an absence."
Victorian Education Minister Ben Carroll also made a last-ditch plea for students to stay in class, saying it was the safest and best place for them to deal with any vicarious trauma.
Israeli forces have been at war in the Hamas-controlled Gaza Strip after a bloody incursion on October 7.
Melbourne rally organisers accuse the federal government of doing nothing to defend the human rights of Palestinians.
They are demanding an immediate end to the war, for Israeli troops to leave the occupied territories and an end to military aid to Israel.
The watermelon is a symbol of the Free Palestine movement because it mimics the flag colours. (James Ross/AAP PHOTOS)
The Melbourne rally is one in a series of national student strikes for Palestinians.
In Adelaide, pupils held a demonstration at Parliament House on Thursday while students in Sydney, Wollongong and Byron Bay will protest on Friday.
NSW Education Minister Prue Car said it was unacceptable for students to skip school to take part.
The protest, to be held at Sydney Town Hall, is being jointly organised by high school and Sydney University activists.
Ms Car said the university students should "stay in their lane" and leave high schoolers to focus on their studies.
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