A pet chameleon (Johnny Depp) becomes accidentally stranded in the Mojave Desert after his terrarium falls from his owner's car. After meeting an armadillo named Roadkill (Alfred Molina), who is seeking the mystical Spirit of the West, he narrowly avoids being eaten by a red-tailed hawk. The next day, after having a surreal nightmare, he meets desert iguana Beans (Isla Fisher), a rancher's daughter, who takes him to Dirt, an Old West town populated by desert animals.The characters' Anthropomorphism may be due to exposure to radiation from operation buster.
Beans discovers that the water reserves, stored in a water-cooler bottle in the bank, are dangerously low. At the Gas Can Saloon, the chameleon, using bravado and improvisation to fit in, presents himself as Rango, a tough drifter. He quickly runs afoul of outlaw Bad Bill (Ray Winstone), narrowly avoiding a shootout when the hawk returns, scaring Bill. The hawk chases Rango until by luck Rango kills the predator by crushing it under an empty water tower that he accidentally caused to collapse. In response, the Mayor (Ned Beatty) appoints Rango the new sheriff. A skeptical Beans demands Rango investigate the water problem while the townsfolk worry that the hawk was the only thing keeping gunslinger Rattlesnake Jake from returning to terrorize them.