"How NOT to Summon a Demon Lord" centers around Takuma Sakamoto, a socially awkward gamer who is transported into the world of his favorite MMORPG, Cross Reverie, as his in-game character, the powerful Demon Lord Diablo. Upon arrival, he is summoned by two girls, Rem Galeu and Shera L. Greenwood, who attempt to bind him with a magical contract. However, due to a magical artifact he possesses, the spell backfires, and the binding instead enslaves the two summoners to him. Despite his overwhelming power, Takuma struggles with his lack of social skills, often relying on his in-game persona to mask his insecurities.

The narrative unfolds as Takuma, now Diablo, navigates this new world, balancing his desire to protect Rem and Shera with his fear of revealing his true self. Rem, a Pantherian (a cat-like humanoid), seeks revenge against the Kingdom of Faltra for the destruction of her village, while Shera, an elf princess, has fled her kingdom to escape an arranged marriage. Together, they form an unlikely party, embarking on quests that intertwine their personal struggles with larger conflicts in the world.

The story explores themes of power, identity, and responsibility as Diablo confronts various adversaries, including corrupt nobles, powerful monsters, and rival Demon Lords. His interactions with Rem and Shera gradually reveal his compassionate side, contrasting with his intimidating appearance and reputation. The series blends action, comedy, and fantasy elements, with a focus on character development and world-building. The dynamic between the three protagonists evolves as they face challenges that test their loyalty, resolve, and understanding of one another. The narrative also delves into the political and social structures of the world, highlighting issues such as racial discrimination and the abuse of power.