Spider-Man: Kizuna takes place on Earth-8989, an alternate universe within the Marvel multiverse where the action shifts from New York City to the fictional Ohakama City in Japan. The story begins when the Green Goblin arrives in the city to enact a new scheme, forcing Spider-Man to pursue him. During the ensuing battle, the Green Goblin detonates a molecular disintegration bomb that strikes the wall-crawler, transforming him into a ghost-like, non-corporeal being who is invisible to almost everyone. The sole person who can see and hear this spectral Spider-Man is a timid fourth-grade boy named Yu Yamato, a shy and overlooked student who loves to draw manga and has difficulty making friends.

As the Green Goblin prepares to attack Yu, the ghostly Spider-Man phases into the boy’s body, activating a device that fully merges them together. This fusion creates a new composite hero named Spider-Man Kizuna, with Kizuna being the Japanese word for bond. Yu is suddenly bestowed with Spider-Man's proportionate speed, strength, and agility, but the fusion also unlocks a unique power based on Yu’s creative imagination and artistic talent. He can manipulate Spider-Man’s webbing to construct objects and even design entirely new costumes, functioning in a manner reminiscent of a Green Lantern’s constructs. While bonded, Peter Parker exists as a disembodied spirit referred to as Spirit Spidey, floating beside Yu to offer guidance, encouragement, and witty commentary as the young hero learns that with great power must also come great responsibility.

The narrative follows a mostly episodic structure centered on Yu’s dual life. While attending school, the Green Goblin distributes special items known as Villain Badges to Yu’s classmates and other citizens. These coins imbue the unsuspecting recipients with the powers and personalities of Spider-Man’s classic rogues’ gallery, transforming them into chibi-style versions of villains such as Little Vulture, Electro Boy, Petit Sandman, and Black Kitty Cat. Realizing that the antagonists are actually victims who have been corrupted, Yu must find the courage to fight them as Spider-Man Kizuna to break the Goblin’s hold, restoring his friends to normal and building genuine bonds with them in the process. Over the course of the series, Yu gradually overcomes his shyness, makes new friends, and develops a possible love interest while trying to keep his secret identity safe and searching for a way to return Spider-Man to his physical body.