"Stitch!: Zutto Saikō no Tomodachi" is a continuation of the "Lilo & Stitch" franchise, focusing on the adventures of the alien experiment Stitch and his bond with a young girl named Yuna Kamihara. The series is set on a fictional Japanese island called Izayoi, where Yuna lives with her family. Stitch, having left Lilo in Hawaii, arrives on the island and forms a close friendship with Yuna, who is kind-hearted but struggles with feelings of loneliness and self-doubt. Together, they navigate challenges while helping others and protecting the island from various threats.

The narrative revolves around Stitch and Yuna's efforts to assist the island's residents, often encountering other experiments created by Dr. Jumba. These experiments, like Stitch, possess unique abilities and personalities, and their interactions with the main characters drive much of the plot. While some experiments are friendly and integrate into the community, others pose dangers that Stitch and Yuna must confront. The series emphasizes themes of friendship, family, and personal growth, as Yuna learns to overcome her insecurities with Stitch's support.

Key characters include Yuna's older brother, Kōji Kamihara, who is protective of his sister but gradually warms up to Stitch, and Penny, a young girl who becomes a close friend to Yuna and Stitch. The series also introduces new antagonists, such as Dr. Hamsterviel, who seeks to capture Stitch and other experiments for his own purposes. The dynamic between Stitch and Yuna remains central, with their bond serving as the emotional core of the story. The series blends lighthearted moments with action and heartfelt drama, maintaining the spirit of the original "Lilo & Stitch" while exploring new settings and relationships.