Lysandre made his debut in the anime in Mega Evolution Special I. Though he was not identified as the caller at the time, he contacted Alain via the Holo Caster, directing him to where a new Mega Stone could be found. He also was seen observing the power of Alain's Mega Charizard X during its battle with Siebold's Mega Blastoise.
He appeared again in Mega Evolution Special II, in which he traveled to Hoenn. He intervened in Alain's battle with Steven, and introduced Alain and Steven properly to each other. It was revealed that in the past, he defeated Alain in a battle over an Ampharosite, then took Alain to Lysandre Labs and recruited him to work in a project to harness the energy of Mega Evolution for peaceful purposes. Lysandre was also the one who awarded Alain his Mega Ring and Charizardite X, though he asked Alain to not tell Professor Sycamore of the research, fearing that people with bad intentions would bring harm to him in order to obtain it. Later, he traveled with Alain, Mairin, and Steven to a ruin, where they uncovered an ancient megalith. However, his research on the megalith accidentally summoned Rayquaza, who destroyed the area. After the encounter with Rayquaza, Lysandre discovered a similar energy reading to the megalith near Rustboro City, and asked Alain to go there and investigate. He also covertly ordered Alain to keep a close eye on Steven, for the HoennChampion had precious information on Mega Evolution.
He reappeared in Mega Evolution Special III, where he gave instructions to Alain and Steven. After Mega Rayquaza defeated both Primal Groudon and Primal Kyogre, he had the megalith, which had reappeared during the battle of the Legendary Pokémon, taken away with his submarine for further studies.
Lysandre appeared again in Mega Evolution Special IV, where he observed Alain's battles against ten Mega Evolution Trainers while his scientists researched the megalith. After Chespie, Mairin's Chespin, who had interfered with the experiments performed on a Zygarde Core, was hospitalized, Lysandre told the victorious Alain that he had to continue gather data on Mega Evolution if Chespie was to recover. He was also shown to be close to Malva, who served as Alain's final opponent. Lysandre also has a major antagonistic role in the XY&Z arc, making appearances in From A to Z! and Meeting at Terminus Cave! studying Squishy alongside Xerosic.
He reappeared in XY105, where he was contacted by Alain via Holo Caster, who wanted to know if Mairin's Chespie's condition had improved or not. Later, he reappeared in the next episode, overseeing the operation to capture Z2 alongside Xerosic. At the end of the episode, he received Z2.
Unlike the games, where Lysandre is Professor Sycamore's former pupil, Lysandre only meets Professor Sycamore for the first time during the events of Mega Evolution Special IV.
- Mienfoo → Mienshao
- Murkrow → Honchkrow
- Gyarados ↔ Mega Gyarados