"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 a head injury. In her previous life, she recalls playing a dating simulation game titled "Fortune Lover," in which the antagonist, also named Katarina Claes, meets a grim fate in every possible storyline. Realizing she has been reincarnated as the game's villainess, Katarina resolves to avoid her destined doom by altering the events of the game.

The narrative unfolds in a fantasy world where Katarina navigates her relationships with key characters from the game, including potential love interests and rivals. These characters include Geordo Stuart, her fiancé and a prince; Alan Stuart, Geordo's twin brother; Keith Claes, her adopted brother; Mary Hunt, a noblewoman; Sophia Ascart, a shy girl with a mysterious aura; and Nicol Ascart, Sophia's protective older brother. Each of these individuals corresponds to a romantic route in the original game, and Katarina's interactions with them often deviate from the game's script due to her proactive efforts to avoid conflict.

Katarina's strategy involves befriending the game's protagonist, Maria Campbell, a commoner with light magic abilities who is central to the game's romantic plotlines. By forming a close bond with Maria and treating others with kindness, Katarina inadvertently creates new dynamics that diverge from the original game's outcomes. Her cheerful and oblivious personality endears her to many, leading to comedic and heartwarming situations as characters develop feelings for her, despite her lack of awareness.

The series blends elements of comedy, romance, and fantasy, with a focus on Katarina's attempts to rewrite her fate. Her efforts to avoid doom often result in unintended consequences, as her actions reshape the relationships and events around her. The story explores themes of self-determination, friendship, and the unpredictability of life, all while maintaining a lighthearted tone. The narrative structure alternates between Katarina's internal monologues, which reflect her knowledge of the game, and the external events that unfold as a result of her choices. This dual perspective creates a balance between humor and tension, as Katarina's attempts to navigate her new life continue to challenge her expectations.