"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 embodies, Katarina, is the primary antagonist destined to face dire consequences—exile, imprisonment, or death—depending on the player's chosen romantic route. Realizing her precarious position, Katarina resolves to avoid her doomed fate by altering her behavior and relationships with the game's key characters.

The narrative unfolds in a fantasy world where magic and nobility coexist. Katarina, initially portrayed as a spoiled and arrogant child, undergoes a transformation as she strives to befriend the game's main love interests and other significant figures. These include Geordo Stuart, her fiancé and a charming prince; Alan Stuart, Geordo's twin brother with a sharp tongue; Keith Claes, her adopted younger brother with a troubled past; Mary Hunt, a kind-hearted noblewoman; Sophia Ascart, a shy and bookish girl; and Nicol Ascart, Sophia's protective older brother. Each character represents a potential romantic route from the game, and Katarina's efforts to prevent her downfall inadvertently lead to her becoming a central figure in their lives.

Katarina's attempts to avoid her fate often result in humorous and heartwarming situations, as her genuine kindness and obliviousness to romantic advances create misunderstandings. Her proactive approach to building friendships and solving problems contrasts with the original game's portrayal of her as a villainess. The story explores themes of self-improvement, redemption, and the impact of one's actions on others, all while maintaining a lighthearted and comedic tone.

As the series progresses, Katarina navigates various challenges, including political intrigue, magical threats, and the complexities of her relationships. Her efforts to rewrite her destiny highlight her resilience and determination, making her a beloved and unconventional protagonist. The anime balances its comedic elements with moments of emotional depth, offering a unique take on the isekai and otome game genres.