The area of Kamiamakusa was part of ancient Higo Province, During the Edo Period it was tenryō territory under direct control of the Tokugawa shogunate and administered from the office of the Nagasaki bugyō.

The city of Kamiamakusa was established on March 31, 2004, from the merger of the towns of Himedo, Matsushima, Ōyano and Ryūgatake (all from Amakusa District).

Kamiamakusa has a mayor-council form of government with a directly elected mayor and a unicameral city council of 16 members.

In terms of national politics, the city is part of the Kumamoto 4th district of the lower house of the Diet of Japan.

Kamiamakusa has a mixed economy dominated by agriculture, commercial fishing and light manufacturing.