The "Borat" star and his actress wife are giving $500,000 to Save the Children to pay for measles vaccinations for children in northern Syria.
They are also donating the same amount to the International Rescue Committee (IRC) to help refugees in Syria and neighboring countries, particularly women and children, with health care, shelter and sanitation.
More than four million refugees have fled conflict in Syria for the relative safety of the neighbouring countries, according to the United Nations.
Millions more have been forced to leave their homes for other parts of the country.
Justin Forsyth, chief executive of Save the Children, said the money would "save many thousands of lives and protect some of the most vulnerable children".
"By allowing us to make their generous donation to Syrian children public, Sacha and Isla are helping highlight the tragedy of the issue today," he added.David Miliband, the ex-British foreign secretary who is president of the IRC, called their gift a "great expression of humanity."
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