In a post-apocalyptic 21st century, a nuclear war has reduced most of the Earth's surface to a barren wasteland and contaminated the global water supply. In this harsh new world, a ruthless dictator named Sanga has built the fortified city of Last Land, where he maintains absolute power by monopolizing the city’s only source of uncontaminated water. When Sanga learns that the neighboring residents of Freedom Village are attempting to dig their own well, he dispatches his underlings to sabotage their efforts.

The wandering master of Hokuto Shinken, Kenshiro, becomes entangled in this conflict after saving Tobi, a rogue informant hired by Freedom Village. Through Tobi, Kenshiro encounters Sara, a beautiful and selfless young woman dedicated to healing the sick and wounded. Kenshiro is astonished to discover that Sara possesses a secret ability to heal by stimulating pressure points, a technique known only to masters of Hokuto Shinken, and she bears a striking resemblance to his lost love, Yuria.

Sara is soon captured by Sanga’s soldiers and brought to Last Land. Sanga has built his regime not only on control of water but also on religious deception, using a young boy named Bista, who can perform apparent miracles, as a false god to enslave the population's will without violence. Sanga now seeks to combine Sara’s miraculous healing power with Bista’s to achieve absolute and eternal dominion.

As Kenshiro and Tobi infiltrate Last Land, they learn that Tobi and Bista are brothers. During a brief confrontation with Sanga, Bista is gravely wounded. Kenshiro must venture out of the city to find medicine for the injured boy. In his absence, a mysterious and powerful warrior named Seiji arrives at Last Land. Consumed by hatred and ambition, Seiji wields Hokumon no Ken, a martial art dangerously similar to Hokuto Shinken. He aims to kill Sanga and seize control of the city for himself.

On his quest for medicine, Kenshiro must cross the treacherous Clifflands, a territory guarded by the Hokumon clan. These warriors practice the forbidden Hokumon no Ken and are bound to a sacred duty: protecting an ancient cache of nuclear weapons from falling into the wrong hands. Kenshiro discovers their secret and understands the heavy burden carried by successors of deadly martial arts.

When Kenshiro finally returns to Last Land with the medicine, he finds the city in chaos, ravaged by a bloody rebellion. Seiji has murdered Tobi, who was attempting to escape with his brother. Overcome with rage and sorrow, Kenshiro confronts Seiji in a brutal, final battle, ultimately defeating the rogue Hokumon master. Though victorious, Kenshiro is filled with grief. Leaving the cursed city behind, he once again sets out alone to shoulder the heavy destiny of the Hokuto Shinken successor.