Later, the new Meiji government believed it would be in their best interests to eliminate Shishio. While they had found Himura to be an idealistic servant of the Imperialist cause, Okubo and other Meiji officials correctly concluded that Shishio was an opportunistic sociopath who would undoubtedly use his vast knowledge of government secrets to plunge the country into turmoil for his own personal gain. Thus, during the Boshin War, Shishio was knocked out from a blow to the head, doused in oil and burned alive by the Ishin Shishi. He survived, sustaining severe damage to his entire body. Even though years have passed since his injuries, he continues to wear bandages day and night. Shishio assembled a group of the best fighters in Japan, called the Juppongatana (Ten Swords), to overthrow the Meiji government. He envisioned a Japan ruled by him, enforcing the principles of Social Darwinism, or what he called "the strong eat the weak". Using this belief Shishio ran a campaign against the Meiji government, as he felt it was too weak to effectively lead the country. Using his motto, he molded an ideological disciple out of Seta Sōjirō, who served as his right-hand man, and the strongest of the Juppongatana. He planned to strengthen the economy with petroleum once he took over the country.
Shishio sends his subordinates to deal with the Oniwabanshū, Kamiya Kaoru, and Myōjin Yahiko while leaving his most powerful fighters to fight Kenshin, Saitō, and Sagara Sanosuke. Shishio sends his lover Komagata Yumi to guide Kenshin. Sōjirō, after his defeat, asked Yumi to tell Shishio about the truth behind Kenshin's Amakakeru Ryū no Hirameki, before leaving him.
Ultimately, Shishio must experience the technique first hand in order to defeat Kenshin, the last remaining block in his conquest. As a result of the damage done to his sweat glands, he could fight for no more than fifteen minutes; otherwise his temperature would continue to rise. Shishio invited Kenshin, Saitō, Sanosuke, and Aoshi to his lair and after having them each fight other strong opponents fought them himself one after the other (with Shishio already knowing their fighting styles.) At the end, his body became so hot, his blood started to evaporate. Yumi attempted to stop Kenshin out of concern for Shishio, but was impaled by Shishio's sword along with Kenshin. Yumi died happily knowing she had finally been of use in battle to her love.
When Kenshin finally decides to try the Amakakeru Ryū no Hirameki against him, Shishio successfully blocks the technique with the knowledge he had obtained from Sōjirō, but he was unaware of the fact that the technique consisted of two parts, the latter of which was not necessary against Aoshi or Sōjirō: The first blow is so powerful it creates a vacuum, paralyzing the opponent temporarily while Kenshin spins around for a second hit. This second strike scores a direct hit on Shishio, however, even after being hit with such a powerful attack Shishio is still able to stand back up. Saito comments that Shishio's ken-ki (fighting energy) is greater than Kenshin's.
In the end Shishio was able to "surpass his limit". However, right when he reached his limit, his temperature skyrocketed—igniting his body fat and oils—leaving him to die by burning alive. As he did, he laughed maniacally, the meaning of the laughter lost to everyone around.
His most loyal servant, Hoji, followed him straight to the grave, slitting his throat in prison when the Meiji Government refused to let him have a public trial. At the end of the Kyoto Arc, Shishio is seen with Yumi and Hoji in Hell. All three walk off into the distance, with Shishio claiming that he will conquer Hell.
His final appearance is in the manga during the Jinchū arc in Kenshin's vision of hell after Kaoru's supposed death. He appears in front of Kenshin and mocks him but the deeply depressed Kenshin didn't care whether he was dead or alive and assumed that Shishio was there to guide him into hell. Shishio agrees to take Kenshin with him, but only if Kenshin were to admit that he was wrong about everything he fought for back in Kyoto. During this vision parts of Kenshin and Shishio's faces are arranged into one showing Kenshin thinking himself the same as Shishio.
Shishio's monstrous strength, durability, and ability to read his opponent place him in at same league as Kenshin. (For example, throughout his fight, Shishio demonstrates the ability to stop Kenshin's Ryushosen using his fingers, dodge and counter Saito's Gatotsu Zeroshiki, see through Aoshi's Kaiten Kenbu Rokuren, and take Sanosuke's Futae no Kiwami without injuries.) Most of his fighting style revolves around powerful strikes that can take out an opponent with one attack. Even his lesser attacks hold tremendous power and force behind them, emphasizing his peerless strength.
Shishio uses Mugenjin to execute techniques referred to by Hoji as "The Three Secret Swords":
Homura Dama (壱の秘剣・焔霊, ichi no hiken: homuradama)- The first Secret Sword, this is the technique Shishio has used the most. Using friction to ignite the human fats that have soaked into his sword over time, this serves to distract the opponent from his swings. The result is being simultaneously burned and slashed. The name translates roughly to "Blazing Soul."
Guren Kaina (弐の秘剣・紅蓮腕, ni no hiken: gurenkaina) - The second Secret Sword technique. He fills his gauntlets with gunpowder, and ignites them with the sparks caused by the Mugenjin. Thus it results in an explosion. Guren Kaina yields a lot of force and is usually performed while his opponent (such as Kenshin or Saito Hajime) is at close range, preferably in his grip. The name translates roughly to "Crimson Lotus Arm."
Kaguzuchi (終の秘剣・火産霊神, tsui no hiken: kagutsuchi) - The final Secret Sword. Kaguzuchi is the ultimate technique in Shishio's arsenal. He activates it by scraping his blade from the base to the tip on the end of the scabbard, creating a miniature fiery cyclone around the blade. The technique is not fully revealed, but it's believed that Shishio starts the fire and then slashes at the enemy, thus he can incinerate them entirely while still cutting them. Before Shishio could utilize the Kaguzuchi, he was countered by Kenshin's ultimate attack, the Amakakeru Ryū no Hirameki. The name of the attack comes from the Japanese fire god Kagu-tsuchi, while the kanji in its name translates roughly to "Spirit God Born in Flames."
Note: In the Rurouni Kenshin: Enjou! Kyoto Rinne video game for the Playstation 2, when Shishio makes contact with his Kagutsuchi, the flames rise upward and form a giant pillar or wall of flames, sending the opponent upward while severely burning him at the same time. Shishio then emerges from the flames as it dissipates. The opponent is seen falling behind him. In the game Jump Ultimate Stars, Shishio can perform the Kagutsuchi and it is listed as one of his support attacks.