"Kamisama Kiss" centers around Nanami Momozono, a high school girl who finds herself homeless after her father abandons her due to gambling debts. While wandering the streets, she saves a man named Mikage from a dog. In gratitude, Mikage offers her his home, which turns out to be a dilapidated shrine. Upon arriving, Nanami discovers that Mikage is actually a land god who has been absent from the shrine for years. He transfers his divine status to her, making her the new deity of the shrine. Nanami, now a god, must navigate her new responsibilities while dealing with the shrine's resident fox familiar, Tomoe.

Tomoe, a powerful and aloof yokai, initially resents serving a human but is bound by a contract to assist Nanami. Their relationship evolves from one of mutual disdain to a complex bond as they face various supernatural challenges together. Nanami's duties as a god involve helping humans and yokai alike, often leading to encounters with other deities, spirits, and mythical creatures. Along the way, she learns about the spiritual world, her own divine powers, and the history of Tomoe, who harbors a tragic past tied to a human woman he once loved.

The narrative explores themes of love, loyalty, and self-discovery as Nanami grows into her role as a deity. Her journey is marked by both comedic and poignant moments, balancing lighthearted interactions with deeper emotional arcs. Key supporting characters include Mizuki, a snake yokai who becomes Nanami's devoted familiar, and Kurama, a tengu who initially poses as a human idol. The story also delves into the dynamics of the spiritual realm, including the politics of the gods and the consequences of breaking divine laws.

As the series progresses, Nanami and Tomoe's relationship deepens, culminating in a romantic connection that transcends the boundaries between human and yokai. The final arcs focus on resolving Tomoe's past and ensuring the future of the shrine, ultimately bringing closure to Nanami's journey as a god and her bond with Tomoe. The series blends elements of fantasy, romance, and comedy, creating a narrative that is both engaging and emotionally resonant.