Having been convicted by the United Galactic Federation for illegal genetic experimentation, Dr Jumba (Zach Galifianakis) is initially imprisoned while his highly destructive and intelligent mutation ‘Experiment 626’, later called ‘Stitch’ (Chris Sanders), is exiled. However, 626 escapes, steals a spacecraft and crash lands in the Hawaiian Islands.

Meanwhile, Lilo Pelekai (Maia Kealoha), a lonely and mischievous young girl, struggles to fit in with her peers after her parents' passing. She is being cared for by her older sister Nani (Sydney Agudong), who is under increasing pressure from a social worker to give up her claim on Lilo and allow her to be placed into care. Nani tries to hold what is left of her family together and prove she can care for Lilo but when Lilo adopts a ‘dog’ from the local shelter, things go from bad to worse. Neither is aware that Stitch, the creature masquerading as a dog, is actually Experiment 626 and that a pair of aliens have been sent to Earth to neutralise the threat he presents.

As Stitch attempts to outwit the aliens sent to capture him, he begins to learn about what it means to have a family, even an imperfect one, and he starts to understand that he is capable of far more than he was created for.