In the 1990s, civilization was ruined as a result of a worldwide nuclear war and many creatures died out. However, mankind survived and entered an age where the strong ruled over the weak, as the few survivors fought over whatever supply of food and uncontaminated water remained in the wasteland of the world.
Kenshiro, successor to the ancient assassination art of Hokuto Shinken, wanders into a village in search of water when he is caught in a trap and imprisoned by the local defense force. In prison, he befriends a young orphaned girl named Rin who nursed him back to health. When the village is attacked by a biker gang and Rin is taken hostage by their leader, Ken breaks free from his cell and rescues Rin, defeating the gang leader with his deadly martial art technique. Kenshiro leaves the village and continues his journey, now accompanied by a young boy named Bat. He becomes involved against the King organization after witnessing the many atrocities they have committed. As he infiltrates the gang's stronghold in the city of Southern Cross, he finds out that the leader of King is his old nemesis, the Nanto Seiken master Shin, the man who engraved the seven scars on Kenshiro's chest and kidnapped his fiancée Yuria. Kenshiro emerges victorious against Shin, only to find out from Shin that Yuria is no longer with him, having taken her own life in despair by jumping off the roof of Shin's palace.
After Shin's downfall, Kenshiro settles in an oasis where he is reunited with Rin, who wandered off searching for Kenshiro after leaving her village. Having acquired a reputation as a saviour after defeating other organizations such as the Golan army and Jackal's gang, Kenshiro is hired by a certain village to serve as their guardian against the Fang Clan, a group of bandits who are terrorizing the locals. With the help of village leader Mamiya, a female warrior who bears a striking resemblance to his lost love Yuria, as well as fellow guardian Rei, the successor to the Nanto Suichōken style, Kenshiro succeeds in vanquishing the Fangs.
However, Kenshiro learns that his three former brothers-in-training in the ways of Hokuto Shinken are still alive and sets off on a journey to find them. He finds out that Jagi, the second youngest, seeks vengeance against him after being disfigured in a past altercation. Jagi is quickly eliminated and Kenshiro goes on to search for the second eldest, a gentle healer named Toki who surrendered the Hokuto Shinken succession after becoming terminally ill due to exposure to nuclear fallout. Kenshiro finds out that Toki is being kept prisoner in the dungeon city of Cassandra, which is controlled by a ruthless warlord known as the Ken-Oh (King of the Fist), who seeks to conquer the post-apocalyptic world by imprisoning everyone who could oppose him. Ken-Oh is in fact the eldest of the four Hokuto brothers, Raoh, who has broken the law of Hokuto Shinken by killing his master after refusing to surrender the succession. After freeing Toki, Kenshiro returns to Mamiya's village to defend it from Raoh, but the long gruelling battle ends in a stalemate and the two warriors are forced to settle their differences another day. Rei is fatally wounded as a result of a previous battle with Raoh and he spends the last few days of his life tracking down his nemesis Juda, successor of Nanto Kōkakuken, who once tormented Mamiya in the past. After defeating Juda, Rei goes on to die, at peace with himself.
With Raoh still recovering from his wounds, another warlord, the Nanto Hōōken successor Thouzer, proclaims himself as the Holy Emperor, having enslaved children in order to construct a mausoleum for himself and his deceased master. Kenshiro joins a resistance movement led by the Nanto Hakuroken successor Shew, who sacrified his eyesight in the past to rescue a young Kenshiro. When Shew is captured and executed by Thouzer, Kenshiro confronts Thouzer and foils his ambitions. With Thouzer now gone, Raoh recovers from his wounds and goes on to resume his reign of conquest. Toki, who is on the verge of dying, uses his remaining strength to challenge Raoh as part of a childhood promise they made to each other, but is ultimately no match for him. Raoh can't bring himself to land a killing blow on his own brother, and spare Toki's life. With Toki no longer in condition to fight, Kenshiro is left as the only one who can defeat Raoh.
The Last General of Nanto appears and decides to side with Kenshiro in order to defeat Raoh, sending out her five guardians, the Goshasei, after Raoh. Kenshiro and Raoh both learn that the General's true identity is Yuria, who was rescued by the Goshasei after her attempted suicide in Southern Cross and was hidden away. After a series of numerous events and battles, Kenshiro emerges victorious over Raoh and he is finally reunited with Yuria. However, the victory is bittersweet, as Yuria, having been affected by radiation sickness, has only a few years left to live. Kenshiro leaves his friends and spends the final few years of Yuria's life with her.
The peace that follows Raoh's downfall does not last long and the world returns to turmoil several years later. Kenshiro rejoins his former travelling companions, Bat and Rin, in their battle against an oppressive Empire, fighting under the banner of the Hokuto Army. The Hokuto Army learns that the Empire has been taken over by an usurper named Jakoh, who has imprisoned the Celestial Empress and has been blackmailing her bodyguard, the Gento Kōken successor Falco, to do his evil bidding. The Hokuto Army fight their way into the central capital and free the Empress, who is in fact Rin's long-lost twin sister Rui. With Rui now freed, Falco turns on Jakoh and kills him, foiling his ambitions.
However, Rin is taken captive by the remnant of Jakoh's forces and is sent off to the mysterious Kingdom of Shura, a brutal land of warriors ruled by three overlords who have all mastered the ways of Hokuto Ryūken, a martial art which branched off from the same clan alongside Hokuto Shinken into the ways of darkness. Kenshiro defeats Han, the third-ranking overlord, who reveals that the Kingdom of Shura was Kenshiro's birthplace. Moreover, Kenshiro also learns that Hyou, the second overlord, is his biological older brother, who lost his memories of Kenshiro after being separated as children and was corrupted into the ways of evil. Following a long gruelling battle, Hyou recovers his memories and reconciles with his long-lost brother. Kenshiro seeks out the highest-ranking and most powerful of the three overlords, Kaioh, who is in fact Raoh's biological older brother. Kaioh plans a conquest to rule the post-apocalyptic world in the name of evil by wiping out the followers of Hokuto Shinken. With Hyou's help, Kenshiro uncovers the sealed testament of the Hokuto Shinken founder, Shuken, which holds the secret to overcoming Kaioh's ultimate technique.
Kenshiro emerges victorious over Kaioh and rescues Rin, leaving her under Bat's care as he goes on an adventure with Raoh's orphaned son Ryu. Meanwhile, a villain named Bolge appears, seeking revenge against Kenshiro for blinding him in a fight a long time ago. Bat brands himself with Kenshiro's seven scars and fights in his place, only to be crucified by Bolge and tortured to near-death. Kenshiro rescues Bat, then fights and kills Bolge, while Rin regains her memories and professes her love to a recovering Bat. Afterwards, Kenshiro leaves and continues his role as the Post-Apocalyptic Savior, defending the weak and fighting off the greedy and violent, as the world finally begins to recover from the nuclear war.