Galen condemned the Nazi “worship of race” in a pastoral letter in 1934, and assumed responsibility for the publication of essays which criticized the neo-pagan Nazi ideologist Alfred Rosenberg and defended the Church’s moral teachings. He also helped draft Pope Pius XI's 1937 Anti-Nazi encyclical Mit brennender Sorge (“With Burning Anxiety”).

In 1941, von Galen delivered three sermons in which he denounced the arrest of Jesuits, the confiscation of church property, and the Aktion T4 euthanasia program which targeted those born with physical or mental defects, and all those regarded by the government as “useless eaters”. These sermons were illegally circulated among German Resistance groups, like the Christian college activists of the White Rose.

Galen suffered virtual house arrest from 1941 until the end of the war. The Nazis intended to hang him at the end of the war. In 1942, Hitler said: “The fact that I remain silent in public over Church affairs is not in the least misunderstood by the sly foxes of the Catholic Church, and I am quite sure that a man like Bishop von Galen knows full well that after the war I shall extract retribution to the last farthing.”

The bishop outlived his persecutors and passed away peacefully on March 22, 1946. A month after his death, the president of the association of Jewish Communities in Germany said: “Cardinal von Galen was one of the few upright and conscientious men who fought against racism in a most difficult time. We shall always honor the memory of the deceased bishop”.