The once-feared Demon Lord Satan of Ente Isla, who had to flee to Earth after being defeated by the hero Emilia Justinia, is now leading a peaceful life in Tokyo under the alias Sadao Maou. Having become a model employee of a local fast-food restaurant, Sadao has to provide for his former generals Alciel and Lucifer who joined him in Japan, as well as avoid confrontations with Emi Yusa—the assumed name of Emilia—and the angels who monitor his actions. Amidst a violent argument between Sadao and Emi, a dimensional portal suddenly appears, carrying a mysterious apple that harbors a toddler named Alas Ramus. To everyone's bewilderment, she imprints on Emi and Sadao, marking them as her parents! After Emi reluctantly agrees to help Sadao take care of Alas Ramus, their semblance of normal life is jeopardized by the appearance of the archangel Gabriel, who comes bearing bad news. He claims that he must take both Alas Ramus and Emi's sacred sword with him—lest the world be destroyed. Unable to accept Gabriel's grim prophecies, the hero and the former Demon Lord need to put their differences aside and unite to protect what they hold dearest.

Professional wrestler Genzou Shibata sports the body of a mountain, but beneath his hulking appearance is a man with an extreme affection for animals. Facing off his opponents in the ring as the legendary Animal Mask, Genzou wins the hearts of crowds everywhere with his iconic tiger persona. During the bout for the title of World Champion against his greatest rival, the Macadamian Ogre, Genzou is suddenly summoned to a fantasy world by a princess. With her kingdom being threatened by a monster infestation, she pleads the wrestler for assistance—to which he answers by knocking her out with a German suplex! Escaping the castle and finding himself stranded in a mysterious land, Genzou decides to begin his career as a beast hunter to capture and befriend creatures far and wide. Joined by the wolf-girl Shigure, the dragon-girl Hanako, and the vampire Carmilla Vanstein, the professional wrestler pursues all kinds of dangerous requests for the sake of fulfilling his dream as a pet shop owner.

An established discipline on par with conventional medical approaches, vocal medicine is the practice of using songs to treat health conditions and injuries. Young people around the world strive to master the art and become healers to help people through the power of their voices. Among the many healers in training is Kana Fujii, a naturally talented singer who was inspired to pursue the profession after a life-changing experience. Along with the driven Reimi Itsushiro and the easygoing Hibiki Morishima, Kana trains at Karasuma Phoniatric Clinic under the stern yet kind mentorship of Ria Karasuma. As they endeavor to achieve their dreams, Kana and her friends meet various colorful healers along the way, discovering that there is much more to vocal medicine than just diligent studying!

Striking fear into the hearts of mortals, the Demon Lord Satan begins to conquer the land of Ente Isla with his vast demon armies. However, while embarking on this brutal quest to take over the continent, his efforts are foiled by the hero Emilia, forcing Satan to make his swift retreat through a dimensional portal only to land in the human world. Along with his loyal general Alsiel, the demon finds himself stranded in modern-day Tokyo and vows to return and complete his subjugation of Ente Isla—that is, if they can find a way back! Powerless in a world without magic, Satan assumes the guise of a human named Sadao Maou and begins working at MgRonald's—a local fast-food restaurant—to make ends meet. He soon realizes that his goal of conquering Ente Isla is just not enough as he grows determined to climb the corporate ladder and become the ruler of Earth, one satisfied customer at a time! Whether it's part-time work, household chores, or simply trying to pay the rent on time, Hataraku Maou-sama! presents a hilarious view of the most mundane aspects of everyday life, all through the eyes of a hapless demon lord.