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The human population has been reduced to 30%, and in the wake of the collapse of global infrastructure, civilization descends into anarchy as the strong rule over the weak with an iron fist, taking for themselves dwindling supplies of food and clean water.
Kenshiro, a man distinguished by the seven scars on his chest in the pattern of the Big Dipper constellation, is but one man living in the post-apocalyptic wastes of the world. One day, while looking for water, he is captured and imprisoned by the defense forces of a nearby settlement. While imprisoned, he befriends two children who called the settlement home, Bat and Lin. Kenshiro learns that Lin had gone mute as a result of witnessing the death of her family, and he touches two points on the back of her skull, granting her the ability to speak again.
Disaster strikes as a group of raiders led by the violent Zeed invade the village, who kidnaps Lin and threatens to kill her unless the villagers surrender their food and water. Kenshiro breaks free from his cell and confronts Zeed, attacking him with a rapid-fire flurry of punches and rescuing Lin. Zeed attempts to kill Kenshiro, but his head suddenly swells and explodes, for Kenshiro is a master of the assassin's martial art Hokuto Shinken; by striking at various vital points on the human body, Kenshiro could kill his enemies from the inside out.
After eliminating the threat Zeed posed on the village, Kenshiro takes his leave. Lin and Bat would leave to accompany Kenshiro on his journey.
Ever since then, Kenshiro has scoured the Earth in search of Yuria and Shin.
In his journeys, Kenshiro crosses paths and fists with a gang of tyrants known as "King". He learns that the gang is led by none other than Shin, who rules over the city of Southern Cross. After killing Shins four lieutenants, Kenshiro makes his way to Southern Cross, where he finds Yuria and Shin. Kenshiro and Shin fight once more, but this time, Kenshiro, driven by rage at his former friend kidnapping his lover and leaving him for dead, emerges victorious.
Kenshiro runs up to Yuria, only to find that it is not the real Yuria, but a life-like statue. Shin despondently explains that Yuria was gone; she had thrown herself from the tower on which they stood and taken her own life, rather than continue to watch as people suffered in Shin's attempts to win her affections. Shin had done everything, from committing all manner of atrocity to betraying his friends, for the sake of Yuria, but now that she was gone, all that he had was worth naught.
As the effects of Hokuto Shinken begin to make Shin hemorrhage blood, Shin, in a final act of defiance, declares that he would not die by Kenshiro's hand before throwing himself from the tower and taking his own life. Afterwards, Kenshiro takes Shin's body and gives him a burial out of respect for his rival.
As it turns out, the "man with seven scars" that Rei was looking for is actually a man named Jagi, someone with whom Kenshiro was all too familiar. Before the nuclear war, Kenshiro and Jagi trained in Hokuto Shinken together, having been adopted as brothers by the previous master of the art, Ryuken. The rules of Hokuto Shinken dictate that only one successor can be named, and all other practitioners must either agree willingly to forego using the art thereafter, or face reprisal. When Kenshiro was named successor, Jagi, in a fit of jealous rage, lashed out at Kenshiro, only to be countered and hit with an attack that left his face horrifically disfigured. Now wearing a mask to hide his disfigurement, Jagi has made it his life's mission to torture Kenshiro, pretending to be Kenshiro (with seven self-inflicted scars to pass as him) and committing atrocities in his name to ruin his reputation.
Kenshiro confronts Jagi, who was also responsible for manipulating Shin into attacking Kenshiro and kidnapping Yuria as another way to torture him. In spite of Jagi using all manner of dirty tricks in addition to Hokuto Shinken to gain the upper hand, Kenshiro manages to defeat Jagi. In his dying moments, Jagi taunts Kenshiro with the fact that his two elder brothers and fellow Hokuto Shinken practitioners, Toki and Raoh, were still alive.
After dealing with an imposter of Toki named Amiba, Kenshiro manages to reunite with Toki in the city of Cassandra, which Kenshiro liberates from the raiders ruling it. Toki had taken to using his own style of Hokuto Shinken as a healing art, and tells Kenshiro that Raoh had become a vicious warlord going by the name of "Ken-Oh", who sought to take over the world.
After liberating Cassandra, Kenshiro and Rei learn that Raoh is marching on Mamiya's hometown. Rei, who was in love with Mamiya, rushes to confront Raoh and fights him, but finds himself outclassed and overpowered effortlessly. Kenshiro fights Raoh, but after a long and grueling battle, the two reach a stalemate. With both men heavily injured, Raoh retreats to recover.
Rei pursues Yuda, intent on killing him for Mamiya's sake. Unfortunately, Yuda manages to avoid Rei, leaving it doubtful that Rei would succeed in bringing Yuda to justice. Toki proposes a risky procedure that would delay the effects of Raoh's attack for another day, one that would causes Rei so much pain that he may wish for death. Rei agrees to undergo the procedure, the process causing his hair to go stark white from the stress and pain. The gambit pays off in the end, as Rei finally manages to confront Yuda and defeat him once and for all.
Not long after Rei's victory, the effects of Raoh's attack finally begin to take hold. Rei says his farewells to Kenshiro and Mamiya before retiring to a hut, so as to spare his friends from watching him die. After Rei's passing, Kenshiro sets fire to the hut he retired to, using it as a funeral pyre.
Shew, another user of Nanto Seiken who lost his eyes during a previous fight with Thouzer, enlists Kenshiro's aid in fighting Thouzer. At first, Kenshiro's attacks against Thouzer are ineffective, his every attempt to strike Thouzer's vital points useless. Thouzer easily overpowers Kenshiro, but Kenshiro is saved by Shew's son, Shiva. Sadly, Shiva is killed, and Thouzer finds the base where Shew and his rebels resided. Afterwards, Thouzer executs Shew by forcing him to carry the peak of his pyramid to the top before shooting him down with arrows, his body becoming crushed beneath the pyramid's peak.
Kenshiro recovers and fights Thouzer once more. This time, he is able to discover why his attacks were ineffective before; because Thouzer was born with his heart on the opposite side of his body, his vital points were similarly inverted. As they fight, Kenshiro learns of the tragic circumstances leading to Thouzer becoming a tyrant; as a child, Thouzer was kind and gentle, but when he was tricked into killing his mentor and surrogate father as dictated by the laws of his branch of Nanto Seiken, the resultant trauma hardened his heart. The pyramid that Thouzer was building with slave labor was made in the loving memory of his mentor. Taking pity on Thouzer, Kenshiro defeats him with an attack that causes Thouzer no pain, but allows him to pass on in peace.
The two brothers fight as Kenshiro watches on. Toki fights valiantly, but tragically, his sickness from radiation poisoning had become so advanced that he no longer had the strength to strike Raoh's vital points. Raoh emerges victorious, but he spares the life of his beloved brother before taking his leave.
For the next few days, Toki continued to work as a healer until he was attacked and fatally wounded by a warrior named Ryuga. An enraged Kenshiro confronts and defeats Ryuga, only learning afterwards that Ryuga was actually Yuria's brother, and that he had committed a form of suicide called kagebara (shadow disembowelment) before the fight. Ryuga wanted to use the last moments of his life to test Kenshiro's resolve, and following the fight and his death at Kenshiro's hands, is certain that Kenshiro would be the one to save humanity.
Kenshiro fights Raoh once more, this time using a new technique: Musou Tensei, an attack that draws its power from the user's sorrow, and the ultimate technique of Hokuto Shinken. In order to gain an advantage over Kenshiro, Raoh kidnaps Yuria and prepares to kill her, hoping his sorrow over her death would awaken the same power within him.
The chase leads them to the old dojo of Hokuto Shinken, where Raoh appears to have killed Yuria. Kenshiro, driven by rage for all of the people who died as a result of Raoh, fights him one last time. This time, he overpowers Raoh and defeats him. Conceding victory to Kenshiro, Raoh makes the proud declaration that he had lived his life without regrets and, with his fist raised firmly towards the heavens, ejects his life force into the sky, parting the clouds and bring light back to the world as his life ends.
After Raoh's defeat, Yuria regains consciousness; Raoh had actually put Yuria into a death-like coma before Kenshiro arrived, having discovered that Yuria was suffering from radiation poisoning. His sympathy for her as he rendered her unconscious awakened the power of Musou Tensei within Raoh. Thanks to Raoh's act of kindness, the progression of Yuria's illness had actually slowed. Having finally reunited with his love, Kenshiro departs with Yuria so that, short though Yuria's life may be, they may spend their time together in peace and happiness.
There is no time to rest, however, as Rin is kidnapped by Jakou's son Jask and taken to the Land of Asura, a country steeped in violence and the birthplace of the Hokuto and Nanto assassin arts. Lin is brought to the country's leader, Kaioh, with the intent of becoming his wife and bearing his children. Kaioh proves to be a dangerous enemy; in addition to being the long-lost elder brother of Raoh and Toki, Kaioh is also a master of Hokuto Ryuken, a sister style to Hokuto Shinken and a particularly dangerous martial art that can drive its practitioners to insanity. When Lin refuses his advances, he exploits a vital point that renders her unconscious and would force her to fall in love with the first person she sees upon reawakening.
Kenshiro confronts Kaioh and is forced to fight Hyoh, Kaioh's lieutenant and Kenshiro's older biological brother. With the help of an ally named Shachi, however, Hyoh's memories of the torment Kaioh put him through, including the death of his fiance by Kaioh's hand, causes him to switch sides and fight against Kaioh's forces, becoming mortally wounded in the process. Kenshiro ultimately defeats Kaioh, and after reconciling with Hyoh as he dies in his arms, opts to take his own life by bathing himself and Hyoh's body in lava, encasing them in stone.
Kenshiro, knowing that Rin held a flame for him yet unable to return her affections, leaves her in Bat's care so she would fall in love with him as a result of Kaioh's exploitation of her vital point and takes his leave. Bat, however, cannot bring himself to live a lie. To that end, he uses his knowledge of Hokuto Shinken to erase Rin's memories and arrange for her and Kenshiro, who is also suffering from memory loss during a particularly awful thunderstorm, to be together while he went to confront one of Kenshiro's old enemies. Kenshiro recovers his memory and intervenes, but Bat is mortally wounded in the fighting. Bat asks Rin to stay with Kenshiro, but Rin, whose memories returned, chooses to stay with Bat instead. Bat's injuries begin to recover, and Kenshiro leaves them to share their lives together.
In his travels, Kenshiro encounters a young boy named Ryu, who is Raoh's orphaned son. After Ryu's adoptive parents are killed by raiders, Kenshiro takes his young nephew under his wing. As the dangers around him put Ryu in danger, Kenshiro leaves him in the care of one of Raoh's former generals, promising to return when he comes of age so that he may fulfill his destiny as the next successor of Hokuto Shinken.