The area of the modern town of Misaki was within ancient Izumi Province and has many Kofun period burial mounds.

The villages of Tannowa, Kyōshi, Fuke and Tanagawa were established within Hine District with the creation of the modern municipalities system on April 1, 1889.

Misaki has a mayor-council form of government with a directly elected mayor and a unicameral city council of 12 members.

Misaki collectively with the cities of Kaizuka, Sennan, and Hannan contributes two members to the Osaka Prefectural Assembly.

In terms of national politics, the town is part of Osaka 19th district of the lower house of the Diet of Japan.