Ogami Ittō, formidable warrior and a master of the suiō-ryū swordsmanship, served as the Kogi Kaishakunin (the Shōgun's executioner), a position of high power in the Tokugawa Shogunate. Along with the oniwaban and the assassins, Ogami Ittō is responsible for enforcing the will of the Shogun over the daimyō (lesser domain lords). For those samurai and lords ordered to commit seppuku, the Kogi Kaishakunin assists their deaths by decapitating them to relieve the agony of disembowelment; in this role, he is entitled and empowered to wear the crest of the Shogunate, in effect acting in place of the Shogun.
After Ogami Ittō's wife Azami gives birth to their son, Daigorō, Ogami Ittō returns to find her and all of their household brutally murdered, with only the newborn Daigorō surviving. The supposed culprits are three former retainers of an abolished clan, avenging the execution of their lord by Ogami Ittō. However, the entire matter was planned by Ura-Yagyū (Shadow Yagyu) Yagyū Retsudō, leader of the Ura-Yagyū clan, in order to seize Ogami's post as part of a masterplan to control the three key positions of power: the spy system, the official assassins and the Shogunate Decapitator.
During the initial incursion, an ihai (funeral tablet) with the shogun's crest on it was placed inside the Ogami family shrine, signifying a supposed wish for the shogun's death. When the tablet is "discovered" during the murder investigation, its presence condemns Ittō as a traitor and thus he is forced to forfeit his post.
The one-year-old Daigorō is given a choice by his father: a ball or a sword. If Daigorō chose the ball, his father would kill him, sending Daigorō to be with his mother; however, the child crawls toward the sword and reaches for its hilt. This assigns him the path of a rōnin, wandering the country with his father as "demons"—the assassin-for-hire team that becomes known as Lone Wolf and Cub, vowing to destroy the Yagyū clan to avenge Azami's death and Ittō's disgrace.
On meifumadō ("The Road to Hell"), the cursed journey for vengeance, Ogami Ittō and Daigorō experience numerous adventures, encountering (and slaying) all of Yagyū Retsudō's children and the entire Kurokuwa ninja clan, and eventually facing Retsudō himself. The first duel between Ogami Ittō and Yagyū Retsudō runs 178 pages—one of the longest single fight-scenes ever published in comics.
Ogami's main weapon is the Dōtanuki battle sword. The Dotanuki smiths cared little for aesthetics, but instead focused on strength, sharpness, and durability in the field. They were renowned for producing blades which would endure the harshest conditions, the most difficult battle field situations and survive to return to battle day after day, year after year.
A crude wooden baby cart which Daigorō rides in, the cart is rigged with all sorts of deadly contraptions. From a repeating Japanese musket rifle stored inside the cart with a front that opens to reveal the weapon, to a iron plate on the bottom of the cart that can withstand musket balls. The cart is also able to float on water and can act as a sled.
Ogami's second weapon is a two piece bamboo staff that connects together with a retractable blade at both ends. Each part is on top of the cart that makes it look like handrails.