In 1939, after the world has been devastated by an invasion of the "Neuroi"—alien war machines of unknown origin—humanity continues to struggle in an uneven fight. With no conventional arms able to pierce through the aliens' hardy armor, resistance forces spare no expense in their search for a way to level the playing field.

Eventually, the so-called "Striker Unit" is designed—a state-of-the-art device utilizing the innate magical powers of young girls and turning them into deadly weapons. The women who are now gathering from all around the world to fight for the survival of the human race are known as "Witches," with the 501st Joint Fighter Wing—the "Strike Witches"—standing at the forefront of the deadly conflict.