"I can talk all right. And I got a good memory. 'Fiora get outta there, get out!' Her screams were music to my ears as my claws slid right through her soft flesh. Like a hot knife through butter!"
—Metal Face, Xenoblade
- Miang Hawwa is eventually revealed to be the true driving force of the game's conflict. Initially Ramsus's wallflower assistant, Miang turns out to be an ancient being with one goal: to prepare humanity for harvest by Deus. The "Eve" of the world, its first woman, Miang has helped to manipulate human history by running an Ancient Conspiracy, causing countless wars and conflicts with countless deaths. Miang demonstrates nothing less than cruel satisfaction at her manipulations, rubbing it in her lover Ramsus's face how he was a failed prototype of Ramsus's rival Fei to break his already fragile mind. Miang awakens Deus and causes the genocide of almost all humanity, in addition to having made it her personal mission to destroy the happiness of lover Fei and Elly's past incarnations every time they reincarnate.
- Bishop Isaac Stone (originally Stein) is an agent of Solaris and one of the darkest and cruelest villains in a game full of soldiers fighting for honor and their beliefs. Having long ago murdered Raquel, the mother of Billy, all because she chose Jesiah over him, Stein continues the conspiracy of the Ethos by taking in orphans and lost people, only to send them to Solaris to be experimented for their secret weapon, and killing any survivors who became Wels or Reapers by sending out priests who he tricked into believing him. After the Ethos tries to break away from Solaris using weapons they found inside an ancient ruin, he begins to massacre them, leaving very few survivors. After being caught up by Billy, a young man who was devoted to Ethos, he gives him a Breaking Speech by telling him the monsters he killed were actually people that Solaris mutated.
- Zanza, the god of Bionis, is the mastermind behind the game's plot and a monstrous excuse of a deity whose insatiable pride ruins countless lives in an effort to prolong his own. Revealed in the sequel to be one half of the scientist Klaus who accidentally destroyed the universe in his experiments, Zanza became a cruel monster who repeatedly exterminated all life on Bionis through the Telethia whenever they drifted away from him, even possessing the noble giant Argas and managing to destroy Agniratha in his attempt to destroy the rival goddess Meyneth alongside all Mechonis. Living on in the Monado after he was sealed away, Zanza murders a young Shulk and the expedition team who discover the Monado before reviving the boy and using him as a host for years. In the final act of the game, Zanza has Shulk killed again by his disciple Dickson to take form once again, transforms the High Entia into Telethia to repeat the extermination of Bionis all over again, and murders both Meyneth and Egil before destroying Mechonis, dismissing everything and everyone as mere bacteria and food to sustain his own cruel existence. Even in spite of all of his hollow justifications for the perpetual cycle of misery he has created, Zanza is revealed at heart to be nothing more than the definition of megalomania and endless arrogance, disgusting almost every single being who knows of his true evil.
- Originally a slimy, cowardly weasel of a man, Mumkhar ends up becoming something far worse entirely. After smugly leaving his close friends Dunban and Dickson to die on the battlefield, he is captured by the robotic Mechon and turned into one of their own, and willingly betrays his people by throwing in his lot with the Mechon and aiding them in their conquest. Going by the name of Metal Face, he leads a squad of Mechon in an attack on Colony 9, slaughters scores of people, and personally murders Dunban's sister Fiora, all out of hatred, envy, and spite towards the man, and gleefully brags about it to Shulk, her Love Interest. Later on, he leads an assault on Eryth Sea, which ends with him killing Sorean, the emperor of the High Entia. After his final defeat at the hands of Shulk and company, he doesn't hesitate to try to murder them all after they decide to spare his life. Fueled entirely by spite and cruelty, Metal Face cements his status as one of the party's most hated enemies.
- Dickson starts the game off as a seemingly helpful mentor and father figure to the protagonists, before revealing himself in the climax to be the vilest of Zanza's disciples and a willing aide to the destruction and recreation of the universe, shooting Shulk to release Zanza into the physical world. Cheerfully asserting that he's Not Brainwashed when they propose he is, Dickson attempts to murder all of his former comrades while helping to lead to Telethia slay all life on Bionis. When the High Entia army shows up to save the heroes, he and fellow disciple Lorithia convert them all into mindless Telethia, including Melia's brother, Kallian. Dickson descends on Colony 6, now the residence of the surviving people of Bionis, with more Telethia, hoping to exterminate them all, taunting Melia and Kallian that he may be Meia's boyfriend in the next life.
- Grandmaster Luxaar is the lord and master of the Ganglion Coalition, a galaxy-wide crime syndicate and tyrannical empire that Luxaar rules with cruel fanaticism. In his quest for "purity" across the cosmos, Luxaar regularly commits genocide against entire races, enslaving those he does not exterminate and often forcing innocents to follow his rule lest he subject their worlds to similar fates. Upon learning of humanity and its connection to the Ganglion's former masters, Luxaar deems humankind a plague deserving of annihilation, and proceeds to lead an assault on Earth that wipe out billions of humans, after which he pursues the survivors across the universe. Luxaar's insane xenophobia comes to end after he massacres his way through dozens of human soldiers and attempts to murder the twenty million sleeping vestiges of humanity.
- Alex is a BLADE who blames the destruction of the Earth on any xeno, regardless of how they're affiliated. Tricking Rook into gathering a number of xenos and attending a seminar that will take place in the wilderness, Alex uses this excuse to attempt murder on the xenos attending as the start of his Final Solution. An opposing group led by Eliza condemns the actions of Alex and his terrorist friends, and in response, Alex tries to have Eliza assassinated during an assembly to advocate human-xeno cooperation. Later, the player finally confronts Alex at Cauldros, where he's seen conspiring with Ganglion forcesthe same Ganglion forces who actually did destroy the Earth—to bring about his genocidal ambitions.
- The egotistical, giggling Dr. Castrofari has children all over Alrest drugged and kidnapped as fodder for his twisted experiments, which aim to forcefully augment his specimens into artificial Blades. When Perun confronts him on his deeds, Castrofari offers to let the children go if Perun surrenders herself as his next subject—only to laugh and confess he'll murder all of the children anyways, giddily announcing his intention to experiment on Perun until shes nothing but a withered husk.