Killswitch Overkill takes place on Gliese 581g, the last remaining colony of the human race. The planet has flooded. It had started with the Great Rotation when an activist group, O.A.K., increased the rotation of the once tidal-locked planet to bring daylight cycles and equality to a world that had never known them. The rotation soon spun out of control, with the sun rising every few hours, and the new heat distribution patterns melted the remaining icecaps to cause the Great Submersion. In the center of the scheme was the late fascist Eduardo Culptos.

The story follows the island-bound Sabrina, who had recently escaped being imprisoned by a sentient crystalline collective called the Bhasura in return for allowing an artificial intelligence called the Id.Entity to hijack her mind. She struggles to resist the Id.Entity's directive to subjugate the population, while ruminating on her vices and the insecurities that caused her to sacrifice her values. Over time, she forgives herself and finds the ideal balance between self-loathing, and exonerating herself of any blame, and she realizes that the way the A.I. manipulates her from within, making her question her reality, is the same way that her lover Eduardo Culptos had done, using her as a means to his ends.

Sabrina is forced to flee the island when it catches fire, but saves a young child, Forest, in the process. She sets off on a journey to find his parents, who are experts in cybernetics and can hopefully discover a way to rid her of the manipulative A.I. that's biasing her choices. She heads to dryland, and after many days without food and water makes it to a large, terrestrial city, Nathril-Xoynsia. There, she meets up with Major Hinesdale, who wants her to steal some sensitive data in return for the location of the boy's parents. She does so.

Sabrina arrives at the supposed home of Forest's parents, only to find an abandoned research lab in the basement that belonged to Aurthur Fitzgerald, a communications expert who had been studying biological communication networks in response to the growing number of Bhasura across the planet. Soon, she realizes she had been led there under false pretenses, as Forest flickers out before her and she reconciles the inconsistencies along her journey to realize that the boy was an A.I. construct, an illusion only she could see. Saving Forest's life had been one of the only good things Sabrina had ever done, and finding out he wasn't real sets her back on her spiritual path to redemption, leading to her wallowing in cycles of cynicism. Desperate, shocked, and alone, Sabrina agrees to outsource all of her emotions to the A.I., giving it nearly complete control over her, though it underestimates how deeply her feelings burn.

The A.I. manipulates Sabrina to corrupt the bio-network and infrastructure of the Town of Amorpha and she does so, but she also arrives on site to help the struggling citizens. Here, she encounters the Fitzgeralds and the Rivenshears, including her arch nemeses Ash and Severum. Knowing that Ash had outsmarted her in cyberspace repeatedly, she solicits her for help, and after reconciling their history, she agrees. The unlikely group teams up, but the A.I. soon jumps ship to a man seeking power who offers much less resistance - Ash's boyfriend Willow Storm Fitzgerald.