Set in a slightly futuristic world where Earth has been invaded and is at war with aliens from another dimension called the Nova, the story follows the adventures of a Japanese boy named Kazuya Aoi who enrolls for training at a special school for genetically modified girls called Pandoras who battle the aliens, and their male partners, called Limiters, who use a special power called "freezing" to limit their opponent's mobility. The protagonist makes the acquaintance of an unusual older girl named Bridgette L. Satellizer who appears to be the most powerful Pandora in her class, but has not yet chosen a male partner to be her Limiter, and in spite of the warnings of all his friends, he decides to be her Limiter.
Goryōkan Academy is a new private senior/junior high school for girls with a vast downtown campus. This highly popular school has "another face" — a secret hidden side. It organizes and trains the special unit Fifth Force to protect the world from invisible supernatural entities known as "Oburi" that are devouring the world. A team of five trained with powers against the Oburi is to be chosen from the student body to perform missions. A new team leader has been appointed to assemble the five students.
The year is 1939 - it was then that the Neuroi appeared. Nobody knows where they came from or what their ultimate agenda is, but the fact remains that their attacks drove people out of their towns and cities. In order to take arms against them, humanity develops a new anti-Neuroi weapon called the "Striker Unit." Using the power of magic to fight against the monsters, this new device enhances and amplifies the power of female magic-wielders. To use this device, young witches from all over the world have been brought together to form an elite task force unit called the 501st Joint Fighter Wing, commonly known as the "Strike Witches."
After discovering that Neuroi are capable of communication with humans and making peace with the nest above Gallia, the Witches squads are now on a mission to re-establish communication when the Neuroi completely vanish after a sudden attack. It is then that they discover a new massive nest that just appeared covering almost all of Europe. Ruthless and without mercy it annihilates allied forces along with many Witches. Word of the attack reaches Fuso and a support battalion is deployed to rescue the survivors. Among the rescue team is the former Striker captain Sakamoto Mio and the now civilian Miyafuji Yoshika who wants to save her dear friends.
In Oshima the happy, carefree 14-year-old Akane Isshiki lived a poor but well-loved life together with her reliable little sister, Momo, who does all the housework, and her grandfather, Kenjirō, a genius inventor who only created useless devices. When the weather is clear, they can see the artificial island, Blue Island, across the sea. In the center of that island rises the revolutionary Manifestation Engine, a discovery that solved the world's energy problems, and leads to some major problems.