An epidemic of unknown origin strikes mankind, killing all adults and rendering the youngsters at the mercy of the vampire kind. Four years later, Yūichirō Hyakuya and his friends make a daring attempt to escape from the vampires, unaware that a mortal trap awaits them.

Four years after escaping, Yūichirō is part of the Japanese Army and is eager to become a member of their special vampire hunting force, the Moon Demon Company, but his reckless behavior leads him to be suspended, until a vampire attacks the local school prompting him to face the enemy against orders.

Yūichirō learns that one of his schoolmates was possessed by a demon and decides to confront him not only in order to save him but to make a contract with the demon and obtain his power. However, he soon learns that subduing the demon will not be such an easy feat.

Instead of dying with the rest of his friends, Yūichirō's best friend Mikaela was transformed into a vampire by Krul Tepes, the queen of the vampires and now works as her aide. Meanwhile, Yūichirō finally begins his training to become a member of the Moon Demon Company.

Wary of the Human Army's rise to power, Krul calls the vampires to war against them, while Yūichirō and his friends are finally selected to attempt to claim a demon weapon for themselves, despite knowing the risks.

After passing the final test, Yūichirō and his classmate Shihō Kimizuki obtain their own Demon Weapons, but when Yūichirō's friend Yoichi Saotome ends up possessed by his weapon, the duo must find a way to bring him back to his senses without killing him.

Yūichirō and his friends introduced to a new member, Mitsuba Sangū, and are then dispatched for his first mission as part of the Moon Demon Company, but when they spot a little girl in distress, Yūichirō ignores orders and rushes to rescue her, despite being warned that he is just being lured into a trap.

After successfully clearing a vampire nest and rescuing the humans held captive, Yūichirō's party sets for the human base in Shinjuku, unaware that the vampires are attacking there. Upon arriving, they come across one of the vampire nobles, and find themselves at mercy of his overwhelming power.

Yūichirō and his companions arrive at Shinjuku to help repel the vampire offensive, while Guren's party spots Mikaela and Ferid, and decides to face them.

Yūichirō and Shinoa get separated from the others and after taking a wounded soldier to be treated, they regroup to assist Guren's party. In the occasion, Yūichirō and Mikaela finally meet again.

Mikaela attempts to escape, taking Yūichirō with him. However, seeing his friends at the mercy of the vampires, Yūichirō goes out of control when a dreadful power emerges from him, threatening allies and foes alike. Shinoa manages to stop him but he falls unconscious.

Yu has been in a coma for five days when Shinoa confronts Guren about special drugs in Yu's pill. He tells her to go and wait for Yu to wake up if she really cares for him. During the seventh day of his coma, Yu wakes up. He finds out that Mika retreated with the other vampires. Once all his friends have gathered he thanks them and apologizes to them. At the end of the episode both Yu and Mika promise themselves they will save the other.

Shinoa spars against Guren before visiting Yu in the library. She tells him about turning humans into vampires. Then, Kureto Hiragi summons Yu to ask him about a vampire spy while torturing Kimizuki and Yoichi to make him tell the truth. Afterward, Yu asks Guren about it and asks if Mika would also be useful to him. In Sanguinem, Mika starves for blood and Ferid recommends halting his growth there. A child offers his blood to Ferid, and Ferid tempts Mika to drink the boy's blood but Mika refuses. Ferid then invites Mika to the Progenitor Council meeting.

Yoichi eliminates five horsemen with one attack, and Yu begins the next step of his training. Yu battles against Asuramaru in his mind and defeats Asuramaru by asking to become friends. At the Progenitor Council meeting, Ferid discusses the battle at Shinjuku and has Mika present a video showing Yu's transformation. Krul strikes at Ferid and intentionally misses. Ferid explains that she cannot kill him. Kimizuki struggles in battle against Kiseki-o and faces memories where he was told to kill his sister. He breaks free and is victorious by remembering Yu's feelings for Mika, who are family even though they are not related by blood. Kimizuki and Yu show off their new techniques, and Shinoa and Mitsuba learn the files on the three boys have been erased.

The child who contacted Ferid Bathory in the previous episode sends a letter via messenger pigeon to Aoi Sangu, who passes it on to Kureto. Shinoa Squad meets, and Kureto Hiragi and Guren Ichinose do the same. Kureto announces his plan to attack and wipe out ten noble vampires in Nagoya before the vampires bring their main army down on Japan in one month. Shinoa reveals that Yu tried to kill her during the battle in Shinjuku, and the squad considers whether to keep following Guren or not. Eventually, they decide to follow him and make their policy to protect their family. Meanwhile, Mika attacks Krul for her blood. Once he calms down, she reveals her plans to him and gives him a secret mission. Shinoa briefs Guren on her squad's success in training, and he gives her new orders. Mika meets with other vampires to head to Nagoya, and Kureto orders potentially lethal experimentation on Mirai Kimizuki.

When the Shinoa squad arrives late, they realize just how serious this mission is for Guren. Knowing this is an impossible mission where many will die, Guren puts his emotions aside and orders his men to not necessarily survive, but to win.

The Shinoa squad and Narumi squad join forces to carry out their mission - to kill the Fifteenth Progenitor, Lucal Wesker. While they succeed in their mission without losing anybody, others were not so lucky. Nine teams fail and were taken as hostages...

The Shinoa squad re-learns the hard cold fact that it's very possible to lose comrades, but there's no time to mourn. They must move on to go rescue the hostages. Right after their departure, Mika and the other vampires arrive to Nagoya as well.

Guren, Shinoa, and Narumi squads arrive at the city hall and see the hostages. Knowing it's a set-up, they still decide to go save the hostages, but Guren and Shinya are way over their heads with Crowley, as they struggle just to run away from him.

Shinoa's squad goes to save Guren, but unfortunately, they run out of time. Reluctantly, they leave him behind and retreat, but Yu just cannot bring himself to do that. Instead, he takes more of the Curse Stimulant Pills to go save Guren himself.

Thanks to his "experimentation," Yu makes a miraculous recovery and once again, goes back to save Guren. Pushing too hard, Yu nearly becomes a demon, but Kimizuki stops him by force. The squad carries Yu out and heads for safety, but then encounters Mika.

Yu and Mika are finally reunited, but the injuries Mika had sustained from fighting the Demon Company threatens his life. Determined to keep Mika alive, Yu tries to persuade Mika into drinking his blood... Even if it means Mika will become a true vampire.

The survivors of the Moon Demon Company get to the rendezvous point, only to find out that their orders are to "standby." Enraged, they decide to ignore the orders to save Guren, when Kureto appears. Apparently, Kureto has something else on the agenda.

Kureto's trump card was Mirai, Kimizuki's younger sister and another Seraph of the End test subject. In order to stop the Japanese Imperial Demon Army, Yu has no choice but to reach out to his inner "trumpet" to tap into the angel's powers.