Mizuno had an outstanding military record and it was expected that he would act as a bulwark on the Sanyōdō highway against possible rebellion by the powerful tozama daimyō of western Japan, such as the Mōri clan.

Fukuyama Castle was complete in 1622 and under Mizuno rule, the area greatly prospered, with numerous public works and civil engineering projects to increase irrigation, open new rice fields and industrial development.

After Mizuno Katsunari's death in 1651, he was succeeded by his son Katsutoshi and grandson Katsusada, and great-grandson Katsuane, who continued his policies, increasing the domains kokudaka to 130,000 koku.

Fukuyama Domain became tenryō territory ruled by a magistrate dispatched by the shogunate, who established a jin'ya in the Miyoshi neighborhood at the eastern end of the castle town.

The shogunate also conducted an extensive land survey, reaching the conclusion that the kokudaka of the territory was actually 150,000 koku due to improvements made under Mizuno rule.

In 1864, Fukuyama Domain was ordered by the shogunate to participate in the First Chōshū expedition, and Abe Masakata, marched to Hiroshima with about 6,000 clan soldiers.

At the end of 1866, as Abe Masakata prepared to depart for the San'in region to participate in the Second Chōshū expedition, the gunpowder stored in Fukuyama Castle exploded and three yagura turrets were lost.

Local Confucian scholar Sando Tokage and chief retainer Miura Yoshitake negotiated a change of allegiance, and the Chōshū forces withdrew before the castle or town were subject to bombardment.