During the World War II German occupation of Poland, Sendler lived in Warsaw (before that she lived in Tarczyn) while working for the city's Social Welfare Department. She started helping Jews a long time before the Warsaw Ghetto was established. Helping Jews was very risky — in German-occupied Poland, all household members were punished by death if a hidden Jew was found in their house. This punishment was more severe than those applied in other occupied European countries.

In December 1942, the newly created Children's Section of the Żegota (Council for Aid to Jews), nominated her (under her cover name Jolanta) to head its children's department. As an employee of the Social Welfare Department, she had a special permit to enter the Warsaw Ghetto, to check for signs of typhus, something the Nazis feared would spread beyond the ghetto. During the visits, she wore a Star of David as a sign of solidarity with the Jewish people and so as not to call attention to herself.

She cooperated with the Children's Section of the Municipal Administration, linked with the RGO (Central Welfare Council), a Polish Relief Organization tolerated under German supervision. She organized the smuggling of Jewish children from the Ghetto, carrying them out in boxes, suitcases and trolleys. The children were placed with Polish families, the Warsaw orphanage of the Sisters of the Family of Mary or Roman Catholic convents such as the Sisters Little Servants of the Immaculate Conception of the Blessed Mary at Turkowice and Chotomów. Some were smuggled to priests in parish rectories where they could be further hidden. She kept lists of the names, hidden in jars, in order to keep track of their original and new identities.

Arrested in 1943 by the Gestapo, she was severely tortured and sentenced to death. The Żegota saved her by bribing the German guards on the way to her execution. She was left in the woods, unconscious and with broken arms and legs. She was listed on public bulletin boards as among those executed. Even in hiding, she continued her work for the Jewish children.