Kiba, an injured lone white wolf, goes to Freeze City following the scent of the Lunar Flower, which is the key to opening Paradise. There he encounters Tsume, Hige, and Toboe, three other wolves who were drawn to Freeze City by the scent of the Lunar Flower and are now living in the city. The wolves encounter Quent Yaiden, a former Sheriff of Kyrios, obsessed with hunting down wolves, and his dog Blue. Cheza, the Flower Maiden who is destined to lead the wolves to Paradise, is being studied at a laboratory under the care of Cher Degré. She is awakened by the smell of wolf's blood. As Kiba and Hige approach the lab to find her, she is stolen away by Lord Darcia the Third, whose people created Cheza.

With the Flower Maiden gone, the wolves have no reason to stay in the city. Despite some initial misgivings and suspicions, they decide to stay together and follow Kiba in his search for the Flower Maiden and Paradise. As they pursue Cheza, the wolves travel through various cities and the remnants of former habitations. Cher joins the city's army to try to recover Cheza, while Cher's ex-husband Hubb Lebowski searches desperately for Cher, and Quent continues his relentless pursuit of the wolves. When Blue eventually encounters Cheza, it awakens her wolf blood from dormancy and causes her to leave Quent and take on her own human illusion. She joins Kiba's pack and travels with them for a while, developing a relationship with Hige. After she becomes separated from the pack, she travels with Cher, while Hubb finds himself traveling with Quent, who is now searching for Blue as well as the wolves.

The wolves and the humans come together in Jaguara's city, where the captured Cheza is being held. In attempting to rescue the abducted Cheza, Kiba, Tsume, and Toboe are captured. Tsume and Toboe are thrown into a dungeon with Hubb while Jaguara attempts to use Kiba's blood to force Paradise to open. Blue and Cher also make their way into the Keep, as does Quent. Darcia interrupts the ceremony as Kiba and the other wolves break free and rush to free the Flower Maiden. Darcia kills Jaguara and battles Kiba as Jaguara's keep collapses around them. The wolves and the humans barely escape with their lives, and Quent is gravely wounded saving Blue from falling debris.

The wolves, now accompanied by Cheza, Cher, Hubb, and Quent, continue trying to make their way to Paradise, pursued by the now insane Darcia. A combination of environmental factors and Darcia's hostility cause most of the characters to die, leaving only Kiba, Cheza, and Darcia alive at the place where Paradise can be opened. Darcia is killed when he attempts to enter Paradise, and Cheza's body disintegrates into seeds. Fatally wounded, Kiba concludes that his quest has failed, but as he lays dying, rain begins to fall and Cheza's seeds grow into thousands of lunar flowers.

At the series' close, Toboe, Tsume, Hige, and Kiba are in their human forms in a modern city. Kiba, walking down a busy sidewalk, begins running towards a lunar flower lying in a puddle in an alley.