When the Coup d’etat of 30 September 1863 brought the more moderate Aizu and Satsuma factions into power, he fled to Chōshū. He returned to Kyoto after the resignation of Tokugawa Yoshinobu in 1867. The first administrative offices (Sanshoku) of the Meiji government were established on 3 January 1868: the Sōsai (President), Gijō (Administration) and San'yo (Office of Councilors). These offices were abolished on 11 June 1868, with the establishment of the Daijō-kan (Grand Council of State). In the new Meiji government, Sanjō was head of the Gijo, Minister of the Right (右大臣) (11 June 1868 - 15 August 1871), and Chancellor of the Realm (Daijō Daijin) (15 August 1871 - 22 December 1885).
He served until the abolition of the daijōkan system in 1885. After the Cabinet system was established, he became Lord Keeper of the Privy Seal of Japan.
In 1889, when Prime Minister Kuroda Kiyotaka and his cabinet resigned en masse, Emperor Meiji only accepted Kuroda’s resignation and formally invited Sanjō to head the government. The Emperor refuse to appoint a new prime minister for the next two months, making Sanō a sole, full-power “Prime Minister concurrently-serving Lord Keeper of the Privy Seal” (内閣総理大臣兼任内大臣) during which time.
After the Meiji Constitution was adopted in 1890, a new system was established: In case of death, incapacitation, resignation or removal of prime minister, a member of the cabinet shall serve as “acting prime minister” (内閣総理大臣臨時代理) until the next prime minister is formally appointed. Today Sanjō’s government is generally regarded as continuation of the Kuroda’s.