Set in a world similar to Earth in the mid twentieth century, Strike Witches tells the story of a fight to protect that world using a combination of magic and technology. The titular Strike Witches, a group of young women with high magical potential, have been gathered together from various nations in a task force to fight against the enigmatic Neuroi. This puzzling enemy force has appeared frequently and without warning in many areas across the world. The weapons of the Neuroi mostly take on forms similar to propeller aircraft but their most troubling tactic is the spreading of a corrosive miasma. Not only do normal humans have no defense against this miasma, but the remnants of the land affected by it are processed by the Neuroi into new weapons, crumbling huge sections of former nations into the sea. As the miasma seems to be unable to spread across large bodies of water, humanity has designated such areas as their main lines of defense.

In order to bring out their potential for use in battle, each Witch equips a unique machine onto their legs: the Striker Unit. With the Striker Unit equipped, they gain the ability to fly and their tapped magical potential provides the strength to utilize weapons far too heavy and powerful for a normal man. Also created is a defensive field that can protect the Witches from the Neuroi's miasma as well as other physical weaponry, making them humanity's trump card in the war. The franchise's main media focuses on the 501st Joint Fighter Wing, spearheading the counterattack in war-torn Europe.