While resting in a forest on the way to Kyoto to defeat Shishio Makoto, Kenshin notices a teenaged girl who defeated four bandits and took their goods. He interrupts her midway through the altercation, but she views him as a bum. Misao was determined to take his sword but Kenshin easily avoids her attacks. Admitting her defeat, she reveals her name as she tagged along with Kenshin and began traveling to Kyoto together. Kenshin often asked her why she likes to steal goods but Misao only answered that she needs money for her journey because she is finding a certain person. They stopped near Shingetsu Village, where they met a young boy named Mishima Eiji. He told them that his village is under control of Makoto Shishio. Accompanied by Saitō Hajime, Kenshin and Misao saved the village. As the story progresses, she became rather attached to Kenshin but becomes angry with him for not depending on anyone else. After Kenshin leaves, she met Kamiya Kaoru and Myōjin Yahiko when she recognises a picture of Kenshin posted on the wall of a restaurant called Shirobeko. However, in the anime Misao runs into Yahiko while she is chasing after Kenshin. Misao takes Kaoru and Yahiko to Kenshin at his Hiko Seijūrō's home. On the way back, Yahiko remembered that he forgot to warn Kenshin about Shinomori Aoshi, who he had seen in Kyoto a few days before, and says it aloud. She had heard of this and demanded them to speak about Aoshi. Therefore, Yahiko and Kaoru mistakenly thought of Misao as their enemy. Misao was shocked at the news of Han'nya's and the others' deaths so she went back to Aoiya for clarification from Okina. She discovered that Okina went to fight Aoshi and leaves immediately. She arrives too late to stop the battle and found Okina barely alive. While tending Okina’s wound in the Aoiya, she received a letter from Okina that said “Misao, in case I died, please forget about Aoshi and lead a normal life.” Speechless and shocked, Aoshi left declaring that he never wishes to see her again. Having difficulty accepting the tragic events, she becomes determined to forget him.

She declares herself as the new Okashira of the Oniwabanashū and refuses to recognise Aoshi as the clan's head any longer. Misao becomes close friends with Kenshin, Kaoru, and Yahiko and helps them fight the agents of Shishio Makoto.

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