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Born in Kochi, Tosa Domain (present-day Kochi city), the second son of country samurai Sakamoto Hachihei. He went to Edo and trained at the Chiba dojo in the Hokushin Ittoryu school, honing his swordsmanship. Though initially drawn to the sonnojoi (revere the emperor, expel the barbarians) movement, he met Katsu Kaishu and became convinced of the necessity of opening the country and strengthening the navy, joining the shogunate's naval training center. In 1865 in Nagasaki he founded the Kameyama Shachu (later the Kaientai), operating it as a combined trading company and naval school. He mediated between the long-hostile Satsuma and Choshu domains and in January 1866 successfully concluded the Satsuma-Choshu Alliance, which became a decisive driving force toward the overthrow of the shogunate. That same year, aboard the Satsuma steamship Yugao, he traveled with Nagasaki merchant's daughter Narasaki Ryo (Oryo) in what is called Japan's first modern honeymoon. In 1867 he drafted the Senchu Hassaku — eight policy proposals that became the blueprint for the transfer of power (Taisei Hokan) — urging the Tokugawa shogunate to voluntarily return governance to the emperor. On 15 November 1867, however, he was assassinated at the Omi-ya inn in Kyoto, reportedly by the Kyoto Shinsengumi or the Mimawarigumi, ending his life at age 31.

He stood out for a free-thinking vision and action that transcended the barriers of domain and social rank. His ability to mediate between the enormous and hostile forces of Satsuma and Choshu is attributed to an independent vision unconstrained by existing interests and prejudices, combined with a warmth that drew people to him. His candid, unadorned style — using spoken language extensively in his letters — is also beloved, and his human appeal resonates powerfully with Japanese people to this day.

Through his two great achievements — mediating the Satsuma-Choshu Alliance and conceiving the framework for the transfer of power — he became the spiritual symbol of the Meiji Restoration. His popularity in contemporary Japan is overwhelming: he has been the protagonist of multiple NHK historical dramas, and his name is inscribed across the country, from Kochi Ryoma Airport onward. His way of life — free-spirited, innovative, and unbound by feudal loyalty — is often cited as a prototype of the modern entrepreneurial spirit.