Lusamine appears in Pokémon Sun and Moon and Pokémon Ultra Sun and Ultra Moon. She is first seen in a picture of a magazine that the player character is reading during the intro sequence. She is formally introduced after the Akala Grand Trial, when Hau and the player travel to Aether Paradise.
As president of the Aether Foundation, Lusamine claims to love all Pokémon, be they native to the Alola region or not. While the player and Hau are conversing with her in the conservation area, an Ultra Wormhole appears, in which Nihilego emerges. In Sun and Moon, after the player battles it, she claims she will find it and love it like the other Pokémon in her care; in Ultra Sun and Ultra Moon, the Ultra Recon Squad immediately show up, upon which Lusamine explains that they are assisting the Aether Foundation in researching Ultra Beasts. Once Hau mentions Lillie, she gives a surprised expression but tries to not acknowledge her, stating that children are better off listening to the adults around them.
Later in the story, Plumeria remarks to Lillie that Team Skull are not the only thieves in Alola, and that Lillie ought to return Cosmog. When Hau, Gladion, and the player arrive at Aether Paradise, all the employees are suddenly hostile to them, including Faba, who had locked down Lusamine's office under her orders. There are also a number of Team Skull Grunts present, implying an alliance.
When the player leaves Hau and Gladion to deal with Guzma, they find Lillie in the same room as Lusamine, with the former begging Lusamine to come to her senses. Lusamine is not fazed by it, and berates Lillie for leaving her and claims she was never her daughter, before teleporting into another room via a pad hidden behind her mirror. Lillie and the player step on the pad too, and teleport into the room her mother went to. When they arrive, Lusamine taunts them to come closer. Afterwards, Lillie and the player are horrified to see that she has a collection of frozen Pokémon scattered about the room, "protected" for all eternity.
Hau arrives, together with Gladion. Lusamine is disgusted by his arrival, as he had stolen Type: Null and ran away from her. He does not try to reason with her, deciding it is impossible at this point. Lusamine, frustrated, exclaims that she gave all her love to her children, only for them to run away. Cosmog is then revealed to be inside a cube, in which Lillie pleads her not to use its power, as it would die. Lusamine, however, acts as though she does not consider her statements, and uses the cube anyway, opening up a large wormhole in the room, and multiple others on the various islands of Alola.
Guzma arrives, asking Lusamine whether the experiment was a success, and Nihilego materializes behind her as well. After being defeated by the player, Lusamine and Guzma jump into the wormhole and disappear with said portal alongside Nihilego.
She is later encountered in Ultra Space, where Guzma has given up working with her because of his newfound fear since Nihilego possessed him, and claims she is immune to reason at this point. Lillie disagrees, and runs off to confront her mother. When they arrive at an open terrace, she is nowhere to be found, only to phase into visibility and appear sitting on a rock in front of them. Lillie continues what she was saying to her mother back at Aether Paradise, along with trying to persuade her to come back to Alola.
Guzma turned out to be correct, as Lusamine says she would rather not come back to Alola, and that Lillie "could not even be that stupid". She boasts about how Ultra Space is beautiful, that Nihilego is all she cares about now, and that Lillie became ugly after leaving her and making friends with the player. Lusamine then turns her attention to the player, in which she immediately battles them, but not before merging with a Nihilego to become a pseudo-beast herself.
After losing, Lusamine becomes enraged and attempts to strike Lillie with one of many large tentacles she has control of. Lillie calls out to Solgaleo/Lunala, who proceeds to roar and emit energy at Lusamine, separating her from Nihilego. Before passing out, she asks Lillie when she started becoming beautiful. At the end of the game, Lillie tells the player she believes Lusamine is getting a bit better, having even tried to go to the player's celebration, and that she has been gently trying to help her mother understand the error of her ways. Lillie then leaves for the Kanto region to seek treatment for her mother from Bill (who, like Lusamine, has been combined with a Pokémon before) in the hopes that it will heal her of the last of Nihilego's poisons.
When spoken to after the victory celebration, Gladion speculates that Lusamine's fixation with the Ultra Beasts may have started when her husband (and Lillie and Gladion's father) Professor Mohn vanished during his study of the Ultra Wormholes and, in an ill-fated attempt to find him, she eventually grew obsessed with the Ultra Beasts to the point of monomania. Lillie's reminiscences on Exeggutor Island show that she recalls that her mother was once a kind and compassionate woman who genuinely cared for her children.