While exploring extra dimensional space for new habitable worlds, a probe belonging to bioengineering section of the Hope's Peak Academy discovers four symbiotic weapons and brings them back to Earth. One escapes in transit, causing the ship to crash in Malaysia, but Hope's Peak recovers the other three and transports them to their research facility in Amestria. Their resident Ultimate Biologist, Yahiro Takigawa, becomes obsessed with bonding the weapons to humans to prepare humanity for Earth's inevitable ecological collapse, and begins illegally experimenting on vagrants, resulting in numerous deaths – including one of the remaining weapons – and attracting the attention of investigative journalist Basara Toujou, who arranges an interview with Yahiro through his girlfriend Miho Naruse, a devil affiliated with Hope's Peak Academy. Against instructions, Basara confronts Yahiro with confidential materials indicating wrongdoing that he stole from Miho's e-mail, leading to them both being fired from their respective jobs and the end of their relationship.
Six months later, Basara is approached by one of Yahiro's classmates and colleagues, Miu Iruma; the Ultimate Inventor, who disagrees with Yahiro's methods and wants to help Basara expose him. With her aid, Basara breaks into Yahiro's research facility to acquire evidence from his crimes, in the process learning that an acquaintance of his, a homeless succubus named Maria, has become one of Yahiro's subjects. Basara attempts to rescue her, but Maria attacks him and the weapon possessing her transfers from her body to his, killing her in the process. Basara manages to escape but soon begins displaying strange symptoms and reaches out to Miho for help. Her new boyfriend, Kyoichi Shiba, examines Basara, discovering the weapon's demonic power and learning that it is vulnerable to noise. Meanwhile, Yahiro kills Miu for her betrayal by exposing her to the remaining weapon, leaving Basara's weapon (called Brynhildr) as the sole surviving specimen.
Basara is attacked by mercenaries employed by Yahiro to retrieve Brynhildr, but the weapon takes over his body – transforming him into a monstrous devil – to repel the attackers. Taking shelter at a nearby lighthouse, Brynhildr communicates with Basara, introducing itself by name, and persuades him to form an alliance, so that he can experience life through Basara, while Basara gets to enjoy the superhuman attributes Brynhildr affords him. Basara uses his newfound abilities to break into his old workplace to turn in evidence of Yahiro's crimes, but is intercepted by SWAT officers on the way out and transforms once again to escape. Miho calls him back to Shiba's office, where Basara learns that Brynhildr is slowly rotting his internal organs. Although Brynhildr claims it is part of their symbiosis, Basara uses an MRI machine to weaken Brynhildr long enough to separate from it, but he is captured by Yahiro's men.
At Hope's Peak Academy, Basara learns that Yahiro has bonded with another devil weapon called Lars and that they are planning to launch a probe into space and bring a legion of demons back to Earth to assimilate the human race. Meanwhile, Miho reluctantly bonds with Brynhildr and breaks into Hope's Peak to rescue Basara, transferring the weapon back to him with a kiss. Basara and Brynhildr merge once again and set out to stop Yahiro and Lars, battling them on the probe's launch platform. As the probe takes off, Basara manages to damage it, causing it to explode, killing Lars and foiling their plan. Shortly after, Basara has mended his relationship with Miho and returned to journalism, while secretly working alongside Brynhildr to protect the city.
In a mid-credits scene, Basara interviews an incarcerated serial killer demon named Rando, who assures Basara that when he gets released from prison soon, there will be carnage.