Hundreds of years ago, the Chinese zodiac spirits and their god swore to stay together eternally. United by this promise, the possessed members of the Souma family shall always return to each other under any circumstances. Yet, when these bonds shackle them from freedom, it becomes an undesirable burden—a curse. As head of the clan, Akito is convinced that he shares a special connection with the other Soumas. While he desperately clings to this fantasy, the rest of the family remains isolated and suppressed by the fear of punishment. Tooru Honda, who has grown attached to the Soumas, is determined to break the chains that bind them. Her companionship with the family and her friends encourages her to move forward with lifting the curse. However, due to confounding revelations, she struggles to find the tenacity to continue her endeavors. With time slowly withering away, Tooru contends with an uncertain future in hopes of reaching the tranquility that may lie beyond all this commotion.

Within the domed city of Romdo lies one of the last human civilizations on Earth. Thousands of years ago, a global ecological catastrophe doomed the planet; now, life outside these domes is virtually impossible. To expedite mankind's recovery, AutoReivs, humanoid-like robots, have been created to assist people in their day-to-day lives. However, AutoReivs have begun contracting an enigmatic disease called the Cogito Virus, which grants them self-awareness. Re-l Mayer, the granddaughter of Romdo's ruler, is assigned to investigate this phenomenon alongside her AutoReiv partner, Iggy. But what begins as a routine investigation quickly spirals into a conspiracy as Re-l is confronted by humanity's darkest sins. Elsewhere in Romdo, an AutoReiv specialist by the name of Vincent Law must also face his demons when surreal events begin occurring around him. Re-l, Iggy, Vincent, and the child AutoReiv named Pino will form an unlikely faction as they struggle to uncover Romdo's mysteries and discover the true purpose of the mythical beings called Proxies.

Koyomi Araragi is studying hard in preparation for his college entrance exams when he begins to notice something very strange: his reflection no longer appears in a mirror, a characteristic of a true vampire. Worried about the state of his body, he enlists the help of the human-like doll Yotsugi Ononoki and her master Yozuru Kagenui, an immortal oddity specialist. Quickly realizing what is wrong with him, Kagenui gives Araragi two choices: either abstain from using the vampiric abilities he received from Shinobu Oshino, or lose his humanity forever.

For centuries, Heaven has required its young angels to live and study among humans in order to become full-fledged angels. This is no different for top-of-her-class Gabriel White Tenma, who believes it is her mission to be a great angel who will bring happiness to mankind. However, Gabriel grows addicted to video games on Earth and eventually becomes a hikikomori. Proclaiming herself a Fallen Angel, she is apathetic to everything else—much to the annoyance of Vignette April Tsukinose, a demon whom Gabriel befriended in her angelic early days on Earth. Vignette's attempts to revert Gabriel back to her previous self are in vain, as Gabriel shoots down any attempt to change her precious lifestyle. As they spend their time on Earth, they meet two eccentric personalities: the angel Raphiel Ainsworth Shiraha, Gabriel's classmate with a penchant for sadism, and the demon Satanichia McDowell Kurumizawa, a clumsy self-proclaimed future ruler of the Underworld. Gabriel DropOut follows these four friends' comedic lives as they utterly fail to understand what it truly means to be a demon or an angel.