A pet chameleon, voiced by Johnny Depp, finds himself stranded in the vast Mojave Desert after his terrarium accidentally falls from his owner's vehicle. In his quest for survival, he encounters an armadillo named Roadkill (voiced by Alfred Molina), who is on a journey to discover the elusive Spirit of the West. Roadkill sends the thirsty chameleon on a path to the town of Dirt, where he can find water.
During his trek through the desert, he narrowly escapes the clutches of a menacing red-tailed hawk and experiences a surreal nightmare. He eventually meets the rancher's daughter, Beans (voiced by Isla Fisher), a desert iguana who takes him to the Old West town of Dirt, filled with a variety of desert animals.
To blend in with the locals, the chameleon ingeniously adopts a new persona as a hardened drifter named Rango. However, he soon finds himself in trouble with the notorious outlaw Gila monster, Bad Bill (voiced by Ray Winstone). Just when a confrontation seems inevitable, Bill is scared away by the hawk, and during the chaos, Rango inadvertently knocks down an empty water tower that fatally crushes the hawk. As a result, the townspeople, eager for a hero, elect Rango as their new sheriff. However, the community remains anxious about the potential return of the outlaw, Rattlesnake Jake (voiced by Bill Nighy).
When Rango discovers that Dirt's water reserves, located in a bank secured in a water cooler bottle, are dangerously low, a skeptical Beans urges him to investigate further. That very night, Rango mistakenly assists a gang of bank robbers, led by the cunning mole, Balthazar (voiced by Harry Dean Stanton), mistaking them for prospectors. The following day, the townsfolk find their water supply stolen, prompting Rango to organize a posse to reclaim it. They discover the bank manager, Merrimack (voiced by Stephen Root), dead in the desert, leading them on an intense pursuit of the thieves, only to find the water bottle empty despite the robbers' assurances of having found it without water.
Rango confronts the mayor (voiced by Ned Beatty), who is amassing land around Dirt but denies any foul play, indicating that he is developing a modern city. The situation escalates when the mayor summons Rattlesnake Jake, who humbles Rango, forcing him to admit that he lied about his past. As a result, Rango roams the desert filled with shame and uncertainty regarding his identity, until he unexpectedly meets the Spirit of the West (voiced by Timothy Olyphant), an elusive figure resembling Clint Eastwood, who drives around in a golf cart. This encounter inspires Rango as the Spirit reminds him, > "No man can walk out on his own story."
Empowered by this revelation, Rango, alongside Roadkill and some magical moving yuccas, unearths the truth behind the town’s water crisis, uncovering that the mayor has been manipulating an emergency shut-off valve in a pipeline leading to Las Vegas. Determined to right the wrongs, Rango recruits the robbers and challenges Jake to a duel, intending to create a diversion that allows the yuccas to work on turning the valve and flood Dirt with the much-needed water, freeing the falsely accused bandits in the process.
However, the mayor, leveraging Beans' safety as leverage, forces Rango to surrender and locks the duo inside the glass bank vault, intending to drown them. Just as the mayor attempts to shoot Jake, believing him to be part of the old guard he wishes to annihilate, he is stunned to find that Rango’s gun is empty. Rango then utilizes the bullet he secretly took to smash the vault's glass, liberating himself and Beans while unleashing a torrent that sweeps the mayor and his henchmen away.
In an act of gratitude, Jake tips his hat to Rango for saving his life before dragging the mayor into the arid wilderness to exact his revenge. Finally, the citizens of Dirt rejoice at the return of their water supply and honor Rango as their newfound hero.
