"Kiss x Sis" centers around Keita Suminoe, a high school student living with his twin stepsisters, Ako and Riko. The series explores the dynamic between Keita and his sisters, who harbor romantic feelings for him despite their familial relationship. Ako is the more reserved and studious of the two, often struggling to express her emotions openly, while Riko is outgoing and bold, frequently taking the initiative in her attempts to win Keita's affection. The siblings' relationship is further complicated by their shared history and the fact that their parents remarried, making them step-siblings rather than blood-related.

The narrative unfolds through a series of comedic and often risqué situations as Ako and Riko compete for Keita's attention. Their antics range from playful teasing to more overt attempts at seduction, creating a blend of humor and tension. Keita, while aware of his sisters' feelings, is often caught in the middle, trying to maintain a sense of normalcy while navigating their advances. The series also introduces other characters, such as classmates and teachers, who add to the comedic and dramatic elements of the story.

Throughout the series, the focus remains on the evolving relationships between Keita, Ako, and Riko, with each episode presenting new challenges and scenarios that test their bonds. The story balances lighthearted moments with more serious undertones, exploring themes of love, family, and the complexities of human emotions. The interactions between the characters drive the plot forward, creating a mix of humor, romance, and occasional drama that defines the series.