In Japan four Zaibatsu Conglomerates sponsor underground death matches between genetically engineered hybrids called Therianthropes who combine the intelligence of humans with the power of animals. A high school girl named Hitomi Uzaki is kidnapped by several men intending to rape her with college student Yūya Nomoto forced to drive the van. Before he can save her, Yūya finds that Hitomi has easily killed her attackers and is forced to drive to an arena for a fight between herself and a lion hybrid. Hitomi wagers that she will win, betting the money that Yūya's organs would fetch if harvested and sold. Hitomi reveals she is a hybrid of a honey badger, the most fearless animal in the world, and easily kills her opponent. Yūya is informed by Hitomi's guardian, Reiichi Shidō, that the Zaibatsu use death matches to attract wealthy investors and gain political and economic influence. Due to Hitomi betting his organs, Yūya is technically the only investor she has allowing her to take part in matches. Hitomi is ordered to protect Yūya, who is given Hitomi’s prize money, 100 million, to bet on future fights. Later, Yuuya is attacked by another Hybrid wanting to learn about Hitomi.

Hitomi arrives to save Yuya. The Hybrid reveals herself as Ryoko Araka, a porcupine Hybrid from the Yatsubishi Zaibatsu, who uses metallic quills as stabbing weapons. She had intended to kill Yuya so Hitomi would have no investor for future matches but decides to kill Hitomi instead. As they battle it is revealed that Hitomi’s honey badger skin is too tough to pierce, even with metal weapons. As Ryoka prepares another attack she is knocked out by a Hippopotamus Hybrid named Ichinosuke Okajima who asks Hitomi to join the Ishida Zaibatsu. Hitomi angrily refuses, until she receives a message from Reiichi, and agrees to fight her next death match as a representative of the Ishida. Hitomi transfers to Yuya’s university where she meets Eruza Nakanishi, a Cheetah Hybrid also from the Yatsubishi. She enrages Hitomi by stealing her underwear, goading her into a fight. They are interrupted by a representative of the Mitsukado Zaibatsu who informs them that as Hitomi is representing Ishida in the next Death Match they are forbidden from fighting beforehand. Unknown observers of the fight reveal that all four Zaibatsu’s are targeting Hitomi and they will most likely strike during the upcoming Death Match.

To hide their Hybrid identities Hitomi and Eruza end up wearing cosplay while students from the photography club photograph them. As Yuya returns home he finds Leo the Lion Hybrid alive, along with Yoko Mitsukado, the granddaughter of the Mitsukado Zaibatsu’s president. Yoko reveals that Hitomi’s guardian, Reiichi, is using the matches to test his Hybrid research and Yuya must participates in the match as Hitomi’s strategist. Yoko is angered when he agrees to take part; having hoped his cowardice would make him withdraw. She decides to take part in the match to ensure Hitomi’s death. As the match requires 3 team members Ichinosuke attempts to recruit another Hybrid but the only one available is Ui Inaba, a Rabbit Hybrid who has never won a match. Ui is attacked by Akemi Kishimoto, a Horned Lizard Hybrid, who has been preventing other Hybrids from joining the Ishida. Ui is almost shot by the blood bullets from Akemi’s eyes but is saved by Hitomi. Ui uses her sensitive hearing to deduce Akemi has a twin sister shooting from another location, allowing Hitomi to defeat but not kill them. As fighting before the match is forbidden Hitomi blackmails the sisters into claiming they were defeated by Ui. Ui, excited by her first ever victory, joins their team.

Before the start of the matches Hitomi’s team meet Nakanishi Taiga, a Tiger Hybrid fighting for the Yatsubishi. His sister, Eruza, decides she wants to kill Hitomi. Reiichi Shidoh is announced as the director of the match on Hotei Island in the Philippine Sea. During the match the hybrids are forced to follow instructions from their investors who move them around the map like pieces on a chessboard. Yuya is initially treated with contempt by his investor opponents who know he has no idea how to play the game but they are forced to take him seriously when he makes an expert move and it is revealed Hitomi has been sending him hand signals via the CCTV monitors, telling him which locations to move her to. Hitomi faces her first opponent, Jerome Hongo, a Bear Hybrid representing the Mitsukado. Hitomi shocks the investors by incapacitating Jerome in less than a second with only a single move. Elsewhere on the map Ichinosuke is placed into a temporary alliance with Shota Yabe, a Gorilla Hybrid from Mitsukado, and Ryuji Shiina, a Crocodile Hybrid from Sumitomo to take down Taiga as a team.

Taiga, using the jungle terrain to his advantage, incapacitates Ryuji and Shota with ease. Eruza is manoeuvred into an area not covered by the cameras, allowing Kaede Kazama, a Gecko Hybrid, and Den Omuna, a Cobra Hybrid, to restrain her with Den planning on raping her. Ichinosuke resolves to die fighting but Taiga is suddenly ordered to move to another area by his investor so he can save Eruza. Before Taiga can leave he is immobilised by Ryuji who traps Taiga’s leg in his jaws. Yuya realises Ryuji had planned this as Hybrids failing to follow instructions within a time limit are executed via explosive collars. Ui is shown alone elsewhere on the island digging a burrow. As Den prepares to rape Eruza he is attacked by Hitomi who had been moved there by Yuya to save Eruza. Yuya is mocked by the investors for making a foolish move to save an opponent. As cameras are moved to the area Hitomi struggles to counter Kaede’s fighting style which utilises the sticky skin on her fingers. Den, having being distracted by Hitomi, has his face slashed by Eruza. Reluctantly deciding to team up Hitomi decides to fight Den while Eruza fights Kaede.

A flashback shows that Den and Kaede were hired to fight in the match by Sumitomo. Yuya learns that when Shidoh took control of the matches he changed the rules so criminals like Den could volunteer to become hybrids and compete. Elsewhere Taiga is suddenly freed from Ryuji’s jaws by Ichinosuke, allowing Taiga to quickly flee to his ordered destination and cancel the explosion that would have killed him. Ryuji swears to kill Ichinosuke. Ui is shown underground digging a complicated tunnel. Hitomi tricks Den and tries to attack on his blinded right side but doesn’t realise Den can still see her using his snake tongue to track her body heat. Hitomi suddenly collapses, paralysed by breathing Den’s venom. Kaede also further transforms into a monstrous Gecko and overpowers Eruza. Den prepares to rape Hitomi but at the last second Hitomi overcomes the paralysis and cuts his genitals off with a single slash. Enraged, Den attacks but Hitomi easily cuts his body in half, severing his tail and incapacitating him. Kaede is left to fight both Eruza and Hitomi alone. As Ichinosuke is about to lose against Ryuji their fight is interrupted by Kido, a hybrid sponsored by Yoko.

Kido is revealed to be Shota's teammate and kills Ryuji with a single punch without transforming into his hybrid form. Kido shocks the investors by mercilessly beating Ryuji’s corpse. Ichinosuke is attacked by Shota, only to suddenly disappear. Kaede is ordered to flee from the area. Eruza and Hitomi happily begin fighting each other. Ichinosuke is shown to have fallen into one of the tunnels dug by Ui who surfaces next to Shota causing her to flee in panic. Eruza pins Hitomi, intending to kill her but instead they begin kissing passionately. They are shown to be drugged by Kaori Rikujo, a Civet Hybrid from Yatsubishi who can produce a pheromone that causes uncontrollable lust. This enrages Yoko who considers such tactics shameful and without honor. Kaede is maneuvered into fighting Taiga but is killed instantly. The investors get more excited watching Eruza and Hitomi until Yoko angrily demands the game continue. Her true intention is revealed, to humiliate Shidoh by beating his hybrids and tactics and ending his influence over her beloved grandfather. Hitomi suddenly breaks free from her lust by focusing on her real lust for Shidoh. She attacks Kaori just as Taiga reaches them.

The Presidents of the four Zaibatsu’s discuss corruptly legalising hybrids, turning matches into a legal business owned solely by the zaibatsu that wins the current game. Shidoh, as the head of the hybrid creation project, has been manipulating events so that no matter which zaibatsu wins, he will be the one with all the power. Taiga insists on fighting Hitomi alone without Eruza or Kaori. Shota manages to trap Ui but damages several trees doing so, forgetting that Kido despises anyone who damages the forest. Kido rips Shota in half but leaves Ui alive. Ui becomes determined to help Hitomi. Taiga reveals that his ultimate goal is to defeat Leo and that Leo is far stronger than people think. Leo had only pretended to lose to Hitomi as her strength was so far below his he didn’t take the fight seriously. Taiga, knowing Leo only seriously fights those he considers his equal, strove to become stronger so he could kill Leo in a fair fight. As Hitomi had insulted Leo by believing herself capable of killing him, Taiga became determined to kill Hitomi for the insult. Hitomi and Taiga prepare to fight to the death.

Yuya thinks about how his life was empty until he met Hitomi. Hitomi takes several hits from Taiga waiting for the best time to counterattack. Ui arrives to warn Hitomi about Kido, not realising Taiga is behind her. As she flees she is caught by Kaori’s pheromones and collapses. Yuya is mocked by the investors for killing Hitomi with his playing style but overcomes his fear by focusing on his friendship with Hitomi and decides to forgo his turn to move Hitomi elsewhere, allowing her to continue fighting Taiga. Hitomi almost manages to counter Taiga’s next attack but is suddenly attacked by Kido’s transformed tail, covered in heavy protective scales. Yuya realizes Yoko emotionally manipulated him into keeping Hitomi in the fight so Kido, who she had likewise emotionally manipulated into hating Hitomi, could kill her. Despite being overwhelmed with lust Ui manages to trick Kaori into falling into one of her tunnels. Hitomi attempts to fight back but cannot cut Kido’s armored skin. As Kido is about to kill Hitomi he is attacked from behind by Taiga, but even he cannot cut Kido’s skin. Everyone is shocked as Kido fully transforms, covering his entire body in thick scale armor, revealing himself as a Pangolin hybrid.

Hitomi is knocked unconscious. Taiga tries to break Kido’s scales but is tricked and loses his right arm. Taiga is saved by Ichinosuke, whose attack leaves Kido vulnerable long enough for Taiga to claw out his right eye. Despite this, both Taiga and Ichinosuke are impaled by Kido. Yoko happily declares her victory for the Mitsukado. However, Hitomi suddenly and explosively awakens and transforms further into her monstrous honey badger form. Shidoh reveals that while most hybrids are genetically modified humans, Hitomi was born with Hybrid DNA, making her an Origin Beast, a perfect fusion of human and animal. A flashback to seven years ago reveals Shidoh first encountered Hitomi living like a wild animal in Hong Kong. By feeding and spending time with her he gained her trust and named her Hitomi, despite numerous injuries to himself. Shidoh’s co-worker, Shibayama, ended up shooting her with a tranquilizer, causing her to collapse in an area controlled by the Liuman Mafia. They are eventually saved from the Mafia by match overseer Shinozaki and Hitomi begins to develop feelings for Shidoh for protecting her. Back in the present Hitomi attacks Kido with vastly superior strength and speed than her previous attacks.

Hitomi manages to slash Kido’s unprotected chest before kicking him into several trees, destroying them. Kido’s flashback reveals he associates plants with his mother. Kido severs Hitomi’s right arm, forcing his protective scales outwards, becoming rows of knives. He beats Hitomi until she suddenly flings her own severed arm into his face as a distraction. During her next attack she smiles, tricking Kido into thinking for a split second that she was his mother, allowing her to thrust her remaining arm down his throat. As Yoko rages for having lost Kido manages to stand up only for Eruza to suddenly slash his throat, finally killing him and making her the Killing Bites Champion. Yoko passes out from shock. Surprisingly, Ui suddenly awakens. As she tries to flee from Eruza she accidentally performs a perfect somersault kick, knocking Eruza unconscious. Overseer Shinozaki declares Ui the Killing Bites Champion. The presidents of the four zaibatsu’s bicker fiercely, accusing each other of cheating. All the lights and monitors suddenly shut down. Unseen to the representatives the island has been infiltrated by Chameleon hybrids under orders to kill all surviving hybrids so the match will be declared void with victory going to no one.

The Chameleon hybrids, under orders from Sumitomo, attempt to kill all surviving hybrids but are stopped by match overseer Shinozaki who publicly declares Ui the victor. The Sumitomo Chairman is killed by Leo while Shidoh instigates a Coup d'état led by himself, the Ishida and Yatsubishi Chairmen and the Anti-Chairman faction of the Mitsukado. They kill Youzan, the Mitsukado president, to give civilian’s access to the Hybrid creation surgery. With her grandfather dead Yoko is left powerless. Leo takes revenge against her for abusing Hybrids by sexually assaulting her and claiming her as his slave. With the match over Yuya returns to his normal life and Hitomi disappears. Two weeks later he receives a message from Hitomi asking him to come to the arena where she first fought Leo. At the arena Yuya thanks Hitomi for giving him confidence in himself while Hitomi thanks him for helping with her matches. Yuya almost confesses his feelings for her, but Hitomi suddenly attacks and kills him, his death having been ordered by Shidoh. As she leaves, Hitomi begins to cry. In the future Hybrids are fully accepted into human society and have their own city built on an island in Tokyo Bay. Non-lethal Killing Bites matches become popular entertainment with many new young hybrids hoping to become champion. Yuya is revealed to be secretly alive and living in Hybrid city.