On the planet Turo, slightly mad scientist Jumba Jookiba (voice of DAVID OGDEN STIERS) has created Experiment 626 (voice of CHRIS SANDERS), a small but deceptively dangerous monster whose sole design is to destroy everything with which he comes into contact. Grand Councilwoman (voice of ZOE CALDWELL), Captain Gantu (voice of KEVIN MICHAEL RICHARDSON), and the rest of the Intergalactic Federation are so aghast at the creature that they order it to be exiled on a desolate asteroid.
Unfortunately for them, the resourceful creature manages to escape his prison transport, steal a spacecraft and uncontrollably leap into hyper-drive, thus eluding his pursuers. 626 then ends up headed toward Earth where he lands in Hawaii. Accordingly, The Grand Councilwoman orders her assistant, Pleakley (voice of KEVIN McDONALD) - whose knowledge of Earth is limited to the fact that it's a restoration habitat for mosquitoes and that humans are not to be harmed because they're part of the food chain - to assist Jumba in retrieving 626.
Meanwhile on Earth, another little troublemaker is creating havoc, but this time around it's Lilo (voice of DAVEIGH CHASE) a young outcast who's being raised by her older sister Nani (voice of TIA CARRERE) after the untimely deaths of their parents. Pressured by social worker Cobra Bubbles (voice of VING RHAMES) to prove that Lilo is getting the best care possible, Nani tries to do that, but the little girl continually makes things difficult for her.
After crash-landing on the island and being captured by animal control, 626 realizes he must change his appearance so as to look less menacing, although he still scares the other dogs in the pound. It's there that Lilo adopts and names the extraterrestrial "Stitch." As the creature tries to maintain a low profile and avoid being detected by Pleakley and Jumba, he still manages to hang out with Nani's friend, David (voice of JASON SCOTT LEE), while also creating his own form of havoc.
That eventually endangers Nani's efforts to keep Lilo with her. From that point on and as Captain Gantu is sent in to assist in capturing him, Stitch finds himself feeling as if he has a family for the first time and does what he must to preserve it.