A pet chameleon (Johnny Depp) becomes stranded in the Mojave Desert after his terrarium falls from his owners’ car by accident. He meets an armadillo named Roadkill (Alfred Molina) who is seeking the mystical “Spirit of the West”. While wandering the desert, he narrowly avoids being eaten by a vicious red-tailed hawk before meeting the desert iguana Beans (Isla Fisher). Beans takes him to Dirt, an Old West town populated by desert animals.
The chameleon presents himself to the townsfolk as a tough drifter named Rango. He quickly runs afoul of outlaw Gila monster Bad Bill (Ray Winstone), but avoids a shootout when Bill is scared off by the hawk’s return. Rango is chased by the hawk until he accidentally knocks down an empty water tower which crushes the predator. The town mayor (Ned Beatty), an elderly tortoise, appoints Rango as the new sheriff. Meanwhile, the townsfolk worry that with the hawk dead, the gunslinger Rattlesnake Jake (Bill Nighy), who is afraid of hawks, will return.