As a young girl, Atsu witnesses her family being massacred by the Yōtei Six led by Lord Saitō, who leaves her to die. Atsu survives and flees Yōtei, becoming a wandering soldier and mercenary for the next sixteen years before returning home to take her revenge against the Yōtei Six. Atsu targets Lord Saitō's lieutenants first: the Snake, the Oni, the Kitsune, the Spider, and the Dragon. She first kills the Snake, but is mortally wounded in the process.

Atsu miraculously survives and recovers from her wound, with witnesses fearfully dubbing her the "Onryō". Returning to her destroyed family home, Atsu begins her hunt for the remaining Yōtei Six. She learns that Lord Saitō is rebelling against the Shogunate, building an army to claim the entire island of Ezo for himself as the self-appointed "Shogun of the North"; the Matsumae clan, who are loyal to the Shogun, have declared war against him. As she travels around Yōtei, Atsu also proceeds to slay as many of Lord Saitō's men as she can, while also assisting the local populace and training under various weapon masters.

As she progresses, she gains a following, dubbed her "Wolf Pack"; Lord Saitō hears of Atsu's exploits, and puts a bounty on her head in hopes of eliminating her. Atsu finds an opportunity to assassinate Lord Saitō at one of his castles but fails. Discovering Atsu's identity, Lord Saitō challenges her to a duel, believing he can recruit her to. Their duel is interrupted when the Matsumae attack the castle, forcing Lord Saitō to retreat. With Lord Saitō back in hiding, Atsu returns to her original quest of slaying the remaining Yōtei Six. Atsu assists the traveling shamisen performer Oyuki to track the Kitsune, and thwart his wolfsbane poison production operation. However, Atsu deduces that Oyuki is the real Kitsune, and the current one is an impostor; Oyuki admits she used to be the Kitsune that served as Lord Saitō's shinobi, but she was disgusted at his murder of Atsu's family and planned to betray him, but she was instead betrayed and replaced as the Kitsune by her disciple Dojun.

Oyuki teaches Atsu her shinobi techniques and together they kill the Kitsune. Oyuki promises to help Atsu slay the rest of the Yōtei Six as part of her atonement. While pursuing the Oni and his raider army, Atsu discovers her younger brother Jubei also narrowly survived the Yōtei Six's attack: rescued by the Matsumae clan, rising in rank to become a samurai officer. He and Atsu hatch a plan to sneak into the Oni's castle with him posing as Atsu's prisoner. However, the Oni sees through their plot, and they are forced to flee, and the Oni attacks the Matsumae camp in retaliation.

Using information from a deserter, Atsu and Jubei sneak back into the Oni's castle, lead a prisoner rebellion, and slay the Oni together. With both the Oni and Kitsune dead, Atsu, Jubei, and Oyuki join forces to go after the Dragon and Spider, Lord Saitō's twin sons, though Jubei is reluctant to trust Oyuki due to her past as the Kitsune. They head to the coast, where they are shocked that Lord Saitō had built a fleet in secret and is assaulting the Matsumae heartland. Jubei reveals he has a daughter, Kiku, and saves her from Saitō troops. While Jubei takes Kiku to the safety of Matsumae Castle, Atsu and Oyuki search for the Dragon and Spider. With the Dragon proving too cautious and elusive to catch, Atsu instead captures the Spider to lure the Dragon out.

The Matsumae organize the Spider's public execution in a deliberate move to draw the Dragon out, but the Saitō forces outmaneuver them with a counterattack on their castle. While Jubei and Oyuki leave to defend the castle, Atsu kills the Dragon while the Spider flees. Despite this, Atsu fails to prevent Matsumae Castle from falling, and Jubei and Oyuki end up going missing. Finding Kiku safe, Atsu evacuates her to her family home. She sees Kiku becoming consumed by the desire for revenge, and regrets prioritizing killing the Dragon over helping Jubei and Oyuki defend the castle.

She tracks down the Spider, who reveals Jubei and Oyuki were captured by Lord Saitō, and when she decides to spare his life, he offers to lead her to his father's castle, having been disowned by him as punishment for letting the Dragon die. Atsu manages to rescue Jubei and Oyuki, but finds out Lord Saitō is waiting for her at her family home to take revenge on her for the death of his sons. With Kiku as his hostage, Lord Saitō challenges Atsu to a duel.

Both Atsu and Jubei battle him, and while they are victorious and kill Lord Saitō, Jubei is mortally wounded and dies shortly after. Six months later, Atsu has given up being the Onryō, and has retired to live a life of peace so she and Oyuki can raise Kiku in Jubei's stead.