On the far-off planet of Turo, a maverick scientist illegally creates a small, indestructible creature with one purpose: to wreak havoc. Named Experiment 626, this creature is incredibly intelligent, strong, and has a penchant for creating chaos. However, during his imprisonment before he's able to unleash his destructive potential, 626 escapes and finds his way onto a spaceship, leading him on a collision course with Earth. After crashing on the Hawaiian Islands, 626 is disguised as a dog to blend in and evade capture by his creator, who is on a mission to retrieve him.

In Hawaii, a young girl named Lilo struggles to cope with the loss of her parents and the challenges of being raised by her older sister, Nani. Their relationship is strained as Nani tries to maintain a stable home while dealing with social workers assessing their family situation. In an attempt to make things better, Lilo adopts what she believes is an innocent dog from the local shelter, unaware that it is actually the alien creature, 626. She names him Stitch and, despite his chaotic tendencies, aims to teach him about loyalty and 'ohana', the Hawaiian concept of family. As Stitch struggles with his destructive programming, the bond between the girl and the alien grows, challenging Stitch to change his ways.