Ms Gates announced her separation from Microsoft co-founder Bill Gates in 2021.
"This is not a decision I came to lightly," Ms Gates wrote in a statement posted to X on Monday.
Her last day of work will be 7 June.
Ms Gates founded the foundation - the largest private body of its kind - in 2000 with her then-husband Bill Gates, the Microsoft co-founder.
In 2021, after 27 years of marriage, the pair announced their separation, but pledged to carry on with their joint philanthropic work.
The Gates Foundation is among the most powerful groups in public health. It spends billions of dollars every year on initiatives aimed at eradicating infectious diseases, reducing poverty and combatting climate change.
According to the foundation's website, the couple donated more than $36bn (£28bn) of their own wealth to it from 1994 to 2018.
"I am immensely proud of the foundation that Bill and I built together," Ms Gates wrote in her statement adding that under an agreement with Mr Gates, she will now have an additional $12.5bn for her own charitable work on women and families.
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