"Monster Musume" is set in a world where humans coexist with various mythical creatures known as "liminals." The story centers on Kimihito Kurusu, a young man who becomes an involuntary host to several liminal girls after a government program places them in his care. The program, called the Interspecies Cultural Exchange Act, aims to foster understanding between humans and liminals by having them live together. Kimihito’s life takes a chaotic turn as he navigates the challenges of living with these unique individuals, each representing a different species.

The primary characters include Miia, a lamia (half-human, half-snake) who is the first to join Kimihito’s household. Miia is affectionate but possessive, often competing for Kimihito’s attention. Papi, a harpy, is carefree and childlike, adding a playful dynamic to the group. Centorea, a centaur, is noble and disciplined but struggles with her feelings for Kimihito. Suu, a slime girl, is curious and adaptable, often taking on different forms. Mero, a mermaid, is romantic and melancholic, often drawing parallels to fairy tales. Rachnera, an arachne (half-human, half-spider), is initially antagonistic but later joins the household, bringing a more mature and teasing presence.

The narrative explores the daily lives and interactions of these characters as they adapt to human society and form bonds with Kimihito. Each episode typically revolves around comedic or dramatic situations arising from their unique traits and cultural differences. The series also delves into the broader implications of the Interspecies Cultural Exchange Act, touching on themes of coexistence, prejudice, and societal acceptance. While the tone is predominantly lighthearted and comedic, it occasionally addresses more serious issues related to the challenges of interspecies relationships. The dynamic between Kimihito and the liminal girls drives much of the plot, with their individual personalities and species-specific behaviors creating a mix of humor, tension, and heartfelt moments.