During a shootout in a saloon, Sheriff Hunt injures a suspicious stranger. The doctor's assistant, wife of the local foreman, tends to him in prison. That night, the town is attacked and they both disappear—only the arrow of a cannibal tribe is found. Hunt and a few of his men go in search of the prisoner and the foreman's wife.

When Rango, a lost family pet, accidentally winds up in the gritty, gun-slinging Western town of Dirt, the theater-loving lizard suddenly finds himself the newly appointed sheriff. Welcomed as the last hope the town has been waiting for, Rango is forced to play his new role to the hilt and uncover the truth behind a looming water crisis—before his act catches up with him.