During the 15th century Sengoku period, Nishio was the home territory for the Sakai clan, based at Nishio Castle. The area eventually came under the control of the Tokugawa clan, and during the Edo period, most of the area was ruled as the Nishio Domain, a minor "fudai" feudal domain under the Tokugawa shogunate. The area prospered as a fishing port, and due to its location on the Tōkaidō highway connecting Edo with Kyoto, although the town itself suffered heavy damage due to a tsunami in the 1707 Hōei earthquake.