Children around the world lost more than a third of the typical 190-day school year because of the coronavirus pandemic, Save the Children said.
The UK-based charity urged governments and donors to take swift action to prevent "an irreversible impact" on the lives of millions of children who may never return to school.
It analysed data compiled primarily by Unesco, the UN educational and cultural organisation, and Unicef, the UN body dedicated to children.
The figures showed that children missed 74 days of education on average because of school closures caused by coronavirus and a lack of access to remote learning.
Using the UN agencies' statistics and data from the US-based Centre for Global Development, the charity calculated that 112 billion school days were lost and the poorest were hit disproportionately hard.
The loss in educational opportunity for children in Latin America, the Caribbean and South Asia was almost three times that missed by pupils in western Europe, it said.
"Almost a year after the global pandemic was officially declared, hundreds of millions of children remain out of school," said chief executive Inger Ashing.
"The year 2021 must be the year to ensure that children do not pay the price for this pandemic.
"We will lose the war against the pandemic if we do not ensure children get back to school safely, have access to health services, have enough to eat and are protected."
Supporting children's safe return to school should be made a priority at this year's meeting of G7 wealthy nations, hosted by Britain in June, said the charity.
That call was echoed by a spokeswoman for Unesco.
"We need a substantial stimulus package to reopen schools safely, targeting the poorest and getting education back on track for the Covid-19 generation," she told AFP.
Save the Children's review of Unesco's research found at the peak of the pandemic last year, 91 per cent of the world's learners were locked out of schools.
The restrictions have widened the wealth and opportunity gap between and within countries, the report said.
"The divide grew between wealthier and poorer families, urban and rural households, refugees or displaced children and host populations; children with disabilities and children without disabilities," Save the Children added.
Ms Ashing said: ‘With vaccines being rolled out, there is hope that we can win the battle against the virus, if all countries can access them. But we will lose the war against the pandemic if we do not ensure children get back to school safely, have access to health services, have enough to eat and are protected. We owe it to children to get this right.”
“At the same time, we need to recognise that children need support as they return to school. Living through this pandemic will have made many anxious and they will have missed out on basic needs, like playing with friends.
"They may also feel enormous pressure to make up for lost education. Children should be able to take their time – it should be a school-by-school, child-by-child process that does not add pressure.”
It interviewed Santiago, a 13-year-old Venezuelan who attends a charity assisted school for children with profound hearing loss.
He said he was "sad, worried, and scared" by the situation.
"I like school. People understand me there. When I can't go to school, I cry and just want to sleep," he was quoted as saying.
Save the Children also paired Unicef research with data from the European Union and US Census Bureau to discover "huge discrepancies" in access to remote learning in wealthier nations.
Students in the United States are more disconnected from the internet than those in other high-income countries, a situation likely to hinder their online learning, it said.
Meanwhile in Norway, 30 per cent of youths aged nine to 18 did not have access to a computer at home, and in the Netherlands this was one of five children.