"My Next Life as a Villainess: All Routes Lead to Doom!" centers on Katarina Claes, a young noblewoman who regains memories of her past life as a Japanese high school student after hitting her head. In her previous life, she recalls playing a dating simulation game titled "Fortune Lover," in which the character she now inhabits, Katarina, is the primary antagonist. In every possible route of the game, Katarina faces dire consequences, including exile, imprisonment, or death, depending on the choices made by the player. Realizing her fate, Katarina resolves to avoid these outcomes by altering her behavior and relationships with the game's key characters.

The story unfolds in a fantasy world where magic and nobility coexist. Katarina, now aware of her role as the villainess, devises strategies to prevent her doom. She focuses on befriending the game's main love interests, including Prince Geordo Stuart, her fiancé, and his brother Alan Stuart, as well as other characters like Keith Claes, her adoptive brother, and Mary Hunt, a rival noblewoman. By treating them with kindness and understanding, Katarina inadvertently shifts their perceptions of her, creating new dynamics that diverge from the game's original plotlines.

As the narrative progresses, Katarina's efforts to avoid her fate lead to unexpected complications. Her genuine and often oblivious nature endears her to those around her, resulting in romantic and platonic affections from multiple characters. Despite her lack of awareness regarding their feelings, Katarina remains focused on survival, often misunderstanding the growing tension among her friends. The story balances humor and lighthearted moments with the underlying tension of Katarina's precarious situation, as she navigates a world where her actions continually reshape the story's trajectory.

The series explores themes of self-determination, friendship, and the consequences of altering predetermined paths. Katarina's journey is marked by her determination to rewrite her fate, even as her actions create new challenges and relationships that defy the original game's structure. The interplay between her knowledge of the game's events and the unpredictable outcomes of her choices drives the narrative, offering a blend of comedy, romance, and fantasy.