In an alternate 1939, Earth is under attack by alien invaders called the Neuroi, who possess overwhelming technological superiority. Conventional weapons are useless against them.
Humanity's only hope lies with young girls known as Witches, who are equipped with special devices called Striker Units that allow them to use magic and fight the Neuroi on equal footing. These Witches form the front lines of defense.
The story focuses on Yoshika Miyafuji, a young, untrained girl who joins the 501st Joint Fighter Wing, the "Strike Witches," in 1944. She must learn to work with her new teammates and master her abilities to help save humanity from annihilation.