During the Edo period, area around present-day Isogo Ward was formerly part of the tenryō territory in Sagami Province controlled directly by the Tokugawa shogunate, but administered through various hatamoto.

Isogo Ward annexed the remaining southern portions of Kuraki District (Kanazawa Town and Mutsuuraso Village) in October 1936.

During World War II, Isogo was bombed twice: once on April 15, 1945, and again during the devastating Yokohama Air Raid of May 29, 1945, during which 692 houses were burned down.

Isogo is largely a regional commercial center and bedroom community for central Yokohama, Kawasaki and Tokyo.

The coastal area is part of the Keihin heavy industrial zone, and has numerous chemical and petrochemical plants.