The name "Yatsushiro" is extremely ancient, and appears in the Nihon Shoki and other Nara period documents.

During the Sengoku period, the area was contested between the Nawa, Sagara, Shimazu and other warlords before coming under the control of Konishi Yukinaga under the time of Toyotomi Hideyoshi.

After the 1600 Battle of Sekigahara, Kato Kiyomasa, the lord of Kumamoto Castle, became the ruler of Higo Province.

On September 1, 1940 Yatsushiro annexed the town of Otago, and villages of Ueyanagi, and Matsutaka and was raised to city status.

Yatsushiro has a mayor-council form of government with a directly elected mayor and a unicameral city council of 32 members.

Yatsushiro, collectively with the town of Hikawa, contributes four members to the Kumamoto Prefectural Assembly.

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

Traditionally, the Yatsushiro Plain is a major producer of rice and igusa, which is the raw material for tatami mats.