In an alternate world, the Cold War has continued to persist for 140 years. As a result, the world was divided into two factions: the West Block, and the East Block. As the Cold War drags on, the tension between the two factions, as well as the amount of nuclear weapons they have, rise. Mylene Hoffman is a female cyborg who is a spy for the West Block. Together with three other agents, Mylene partakes in various missions issued by her superiors.
Index is still a fugitive and many powerful magical organizations and individuals want to take her to use the books in her memory, eliminating her in the process. War between those organizations is also starting to emerge. Index can only rely on her friend Tōma, who has always protected her, along with Misaka and other friends from the Academy.
Godō Kusanagi is a 16-year-old high school boy, who once killed the god "Verethragna" and acquired the title of "Campione" ("God Killer") when he was 15. Erica Brandelli is a 16-year-old Italian girl, who is a "Great Knight" of the magic society "Bronze Black Cross" and had fought together with Godo to defeat Verethragna. Godo doesn't like fighting but his title of "Campione" makes him get involved in battles against other Campiones and uncontrollable gods.
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.