"Kiss×sis" centers on Keita Suminoe, a high school student living with his father, stepmother, and twin stepsisters, Ako and Riko. The series explores the unconventional dynamics of their relationships, as Ako and Riko harbor romantic feelings for Keita, despite being his stepsiblings. The story unfolds through a series of comedic and often risqué situations, as the sisters frequently attempt to seduce Keita, blurring the lines between familial and romantic affection.

Keita, while often flustered by his sisters' advances, struggles with his own feelings and societal expectations. The narrative delves into his internal conflict, balancing his desire to maintain a normal sibling relationship with the growing tension caused by Ako and Riko's persistent efforts. The series also introduces other characters, such as classmates and friends, who add to the comedic and dramatic elements of the story.

Ako is characterized as the more reserved and studious of the twins, often hiding her feelings behind a calm demeanor, while Riko is more outgoing and openly affectionate, frequently initiating bold attempts to win Keita's attention. Their contrasting personalities create a dynamic interplay that drives much of the series' humor and emotional moments.

The plot progresses through various school and home life scenarios, including cultural festivals, study sessions, and family outings, all of which serve as backdrops for the evolving relationships between Keita, Ako, and Riko. The series balances its comedic tone with moments of introspection, as the characters navigate their complex emotions and the societal taboos surrounding their situation.

"Kiss×sis" is notable for its blend of romantic comedy and ecchi elements, with a focus on the interplay between the main characters and the challenges they face in reconciling their feelings with their familial bonds. The narrative maintains a lighthearted approach while occasionally touching on deeper themes of love, loyalty, and the boundaries of relationships.