Later, Mayuri joins Byakuya Kuchiki, Kenpachi Zaraki, Retsu Unohana, and their subordinates in Hueco Mundo. He saves Uryū and Renji Abarai from Szayel Aporro Granz, having an advantage against the Espada due to a bacterium he implanted in Uryū during their last fight that analyzed Szayelaporro's abilities. After defeating his controlled Zanpakuto while his opponent uses Nemu's body to reconstitute himself, Mayuri felt disappointed by the Arrancar's claims to have become a perfect being. As Szayelaporro's new body is paralyzed from exposure to one of the serums in Nemu's body dubbed the Superhuman Drug, Mayuri very slowly kills him while giving him a lecture on why scientists shouldn't claim or even want perfection. Soon after, Mayuri investigates Szayelaporro's laboratory to take what he can for his research before healing Uryū and Renji, followed by sending Ichigo Kurosaki and Unohana through the Garganta to the Fake Karakura Town. While explaining to Byakuya that he is more interested in seeing what specimens Hueco Mundo offers to him, Mayuri notes that he does have faith in Ichigo's ability to end the war. Once the fight against Aizen is settled, Mayuri attempts to seal off the Fake Karakura Town with their allies still inside but is stopped by his subordinates.