Sagara Sanosuke left home at an early age to join the Sekihō Army (Sekihō-tai), leaving behind his father (Kamishimoemon), his mother (Naname), and his younger sister (Uki) who adored him. He would return home years later to discover that his mother was dead, having died a couple of years after the birth of his younger brother, Ota, who immediately began to admire Sanosuke for his bravery and boldness. Sanosuke would also find out that his family name was now Higashidani, although he would never use it himself. His sister, after Sanosuke's disappearance and then her mother's death, became overprotective of her younger brother and father, who worked as a local merchant and farmer with the infamy of being a local fighter. Ota, after Sanosuke leaves his family again, would eventually follow his brother's advice and train at the Kamiya Kasshin-Ryū style dojo to become strong.
The Sekihoutai fought for the imperial alliance at the end of the Tokugawa regime and Sanosuke admired his captain, Sagara Sōzō and took the family name Sagara from him. The Sekihō Army were on assignment to spread word of the halving of taxes proclaimed by the revolution. However, when the revolutionary government encountered financial problems, they labeled the Sekihoutai as frauds to bury their promises. This setup was engineered by Shindō Tatewaki, a former officer in the imperial alliance. The Sekihoutai were designated scapegoats and to be executed; Sanosuke was the only survivor, other than his friend Tsukioka Katsuhiro. The exact circumstances of Sōzō's death differ between the animated version and the manga; in the manga Sanosuke realized he had been killed after seeing his decapitated head on display as a warning, while in the anime a wounded Sōzō pushed Sanosuke to safety off a cliff in order to save him before dying himself.
Full of anger and bitterness, Sanosuke made a living as a fighter-for-hire who bore the nickname "Zanza" derived from his weapon, the zanbatō. Sanosuke's sword, the heaviest katana ever made in the Rurouni Kenshin universe, originates from the Ōnin Struggle. Due to wear the blade no longer has an edge. Sanosuke uses the sword to smash and crush.
Hiruma Kihei and Gohei hire Sanosuke to kill Himura Kenshin, but after the former assassin defeats Sanosuke and Sanosuke learns of the truth of Kenshin's no-kill approach, Sanosuke becomes a valuable ally. He later adopts a boxing-like fighting skill, known for the strength of his right fist. Because the zanbatō broke during the fight, Sanosuke no longer wields it on a regular basis, using only one more time in the manga to defend the Kamiya dojo during the Jinchu arc.
At the end of the manga series, Sanosuke leaves Japan to avoid becoming wrongfully arrested and travels the world. He is not heard from until five years later during a reunion of the Kenshin-gumi, in which he tells them via a letter that he is in Mongolia and will stay there for a while before heading back to Japan.