At least 652 children died - 255 of them in or near a school - last year, a 20% jump from the number killed during 2015, Unicef said.
The figure includes only formally-verified deaths, meaning the number could be far higher.
Unicef believes more than 850 children were recruited to fight in 2016. "The depth of suffering is unprecedented," said Geert Cappelaere, Unicef regional director for the Middle East and North Africa speaking from Homs, Syria.
"Millions of children in Syria come under attack on a daily basis, their lives turned upside down."