Ghetsis first appears in Accumula Town trying to rally its citizens. After that, he appears at several points in the game trying to warn the citizens of the oncoming change and is often the one that comes to rescue other Seven Sages if they are nearing arrest. After the player and Alder come to the Relic Castle he is already there and tells them that if they are to battle N, they must retrieve the Light/Dark Stone. He also appears making a similar speech to his one in Accumula Town in Opelucid City. He later appears at the castle during N's takeover and taunts the player before battling N. After the player defeats N, he reveals he has been using N and revived Zekrom/Reshiram for N to use, and calls N a disappointment. He reveals that his and Team Plasma's motive for stealing Pokémon was a lie all along and that Ghetsis wanted to ensure that he was the only person in Unova with Pokémon, so he could dominate the region (this was previously foreshadowed by him referring to himself during speeches referring to Team Plasma's goals before correcting himself and saying Team Plasma). According to a Grunt in the castle, he was even learning of ways to manipulate hearts of people. Alder and Cheren both hear the truth from Ghetsis. Ghetsis battles the player in a rage, despite N's protest. After the battle, Alder and Cheren arrest Ghetsis and take him away. He is not seen again in this game.
When the player meets the Shadow Triad for the final time, it is revealed that they rescued Ghetsis from captivity and that he is currently on the run. He has lost everything, including his Pokémon, and only the Shadow Triad are still loyal to him. For some reason, he has ordered the Shadow Triad to stop looking for him.
In Pokémon Black and White 2, Ghetsis is revealed to be the true mastermind behind the new Team Plasma, which had seemingly been led by Zinzolin, Colress and the Shadow Triad. After Colress is defeated, Ghetsis confronts the player and angrily denounces Colress as being more interested in science than in Team Plasma's ambitions even after being appointed as the organization's official leader. He leaves the player to fight the Shadow Triad while he enters the Giant Chasm with Kyurem. By the time the player catches up with him, Ghetsis has prepared his plan to freeze all of Unova. He summons Kyurem to his side and orders it to use Glaciate on the player, only for N to arrive with Zekrom/Reshiram and interfere. This however was part of Ghetsis's plan, and while berating N for causing what will happen to Unova as a result of N's refusal to be his pawn in the previous games, Ghetsis uses the DNA Splicers to forcibly revert Zekrom/Reshiram into its stone form. Kyurem then fuses with the stone, creating Black Kyurem/White Kyurem. Ghetsis challenges the player to fight Black Kyurem/White Kyurem, preventing it from being captured via a signal from his cane that disrupts the function of Poké Balls. Upon the defeat of Kyurem, its Absofusion is reversed, separating it back into Kyurem and Zekrom/Reshiram. Ghetsis flies into a rage and attacks the player, starting a final battle. When he is defeated, he suffers a mental breakdown and violently rejects the compassion N shows him. The Shadow Triad take him away from the Giant Chasm and later inform the player that Ghetsis is no longer mentally capable of any further criminal deeds, finally ending his threat to Unova.
Ghetsis, as he appears in Pokémon Black and White Versions, appears as a member of Team Rainbow Rocket in Pokémon Ultra Sun and Ultra Moon. This Ghetsis, like the other members of Team Rainbow Rocket, was brought from a world where his plans succeeded. After arriving in the game's world, Ghetsis began pondering the reasons for his being summoned. He then concluded that his purpose was to travel between worlds and liberate all Pokémon from people, consolidating power in himself so that he may rule over all of existence. For this purpose, he intends to use Giovanni as a pawn, reasoning that a human with an evil nature will be easier to manipulate than a freak without a human heart. Refusing to allow the player to reach Giovanni and interfere with his plans, Ghetsis challenges the player, using Zekrom/Reshiram as part of his team. After being beaten, he refuses to accept his loss and strikes Lillie, taking her as a hostage. Ghetsis demands that the player throw down their Poké Balls if they wish to ensure Lillie's safety. No matter the player's choice, Colress appears in the room, rescues Lillie, and recognizes Ghetsis as not being the Ghetsis he knows. Ghetsis recognizes him as the Colress of the game's world, but fails to understand why he is opposing his plans, prompting Colress to declare that he simply hates Ghetsis altogether. Colress then utilizes a newly-developed device to warp Ghetsis back to his original world.