When World War II broke out with the Nazi invasion of Poland in September 1939, he fled east with other members of Hashomer Hatzair. Soon he was in trouble with the Soviet authorities when he was caught trying to open a smuggling route for Jews through Romania into British Mandate Palestine.
After his release Anielewicz traveled back and forth between the Warsaw Ghetto and Vilna, Lithunia, where there were many politically active Jews and Jewish youth groups.
In Warsaw, he, along with his girlfriend Mira Fuchrer, carried on with political and educational activies and was soon involved in various anti-fascist organizations and Jewish self-defense groups.
In November 1942, Anielewicz became the leader of the Jewish Fighting Organization (ZOB), which consisted of members of various youth groups. The group targeted both Jewish collaborators, such as the Nazi supervised Jewish police force, as well as Nazis, and was emboldended by mass deporations and arrests leaving 60,000 residents in the ghetto from a high of 350,000.
The organization was able to gain arms from the Polish (Aryan) side of the city, and when the Nazis prepared for the 2nd big wave of deporations, in January 1943, it's members rose up. Anielewicz commanded one of the main street battles. Many members of the group were killed but the revolt slowed down the Nazis greatly.
On April 19, 1943 the final deportation and resistance began. Heavily outnumbered and outgunned, the Jews held out for weeks despite repreated calls for their surrender. Nazis were forced to go from house to house, burning them as they progressed.
On April 23, Anielewicz wrote the following letter to a friend:
Be well, my friend! Perhaps we will see one another again. The most important thing is that my life's dream has come true. Jewish self-defense in the ghetto has been realized. Jewish retaliation and resistance has become a fact. I have been witness to the magnificent heroic battle of the Jewish fighters
On May 8, Anielewicz, Mira Fuchrer, and several comrades were killed when their headquarters bunker was overrun by Nazis. Some sources suggest Anielewicz and Fuchrer committed suicide.
The resistance lasted approximately one month.