In 1858 Hisamitsu succeeded as daimyo (head) of Satsuma han in western Kyushu, one of the largest feudal domains into which Japan was then divided. At that time the country was in the midst of a grave crisis over Western demands that Japan end its two centuries of seclusion and open its ports to international trade. That crisis revived sentiment for restoring the emperor as the centre of government. Hisamitsu accordingly demanded that shogunal officials grant more power to the emperor and to the important feudal lords like himself, who had previously been denied participation in the central government. The appointment of the Hitotsubashi clan leader Tokugawa Yoshinobu as shogunal guardian signaled the acceptance of Hisamitsu's proposals. To give Yoshinobu the opportunity to work out a new program, Hisamitsu helped suppress the extremist leaders who had gathered around the emperor and who were harassing the shogun.

On Sept. 14, 1862, as Hisamitsu was traveling to the court with his retinue, his followers attacked four Britons who rode past the procession without paying proper respect to Hisamitsu. One was killed and two others were wounded. Britain's demand for a huge indemnity precipitated a major crisis. The shogun agreed to pay £100,000, but the Satsuma han refused to pay anything. The British then attacked and partly leveled the Satsuma capital, Kagoshima. Realizing that British strength was far superior, Hisamitsu offered to pay £25,000 and to punish the culprits if they could be found.

Early in 1864, Hisamitsu and several other daimyo were appointed as members of a new governing council composed of representatives of the court and of the shogun. But a dispute between Yoshinobu and Hisamitsu soon broke up the conference and ended hope of a political compromise. After his return to Satsuma in March, Hisamitsu increasingly came under the influence of his vassals Saigō Takamori and Ōkubo Toshimichi. In 1867 the three were instrumental in inducing the shogun to resign, thereby paving the way for the Meiji Restoration in 1868. Hisamitsu subsequently participated in organizing the new government. His position was largely symbolic, however, and he soon retired.