Due to the thick layer of volcanic ash (from the Prevo and Sawritski volcanoes), archaeological expeditions on the island could not discover any monuments of the Okhotsk culture. The first people to settle Simushir in modern times were the Ainu, who called it Simusir (“Big Island”). In the 18th century, Simushir was nominally claimed by the Japanese clan Matsumae (jap. 松前氏 Matsumae-shi).

In 1635, the Matsumae clan commissioned the samurai Murakami Hironori to explore the territories claimed by the principality. In 1644, the Japanese created the first surviving depiction of Simushir, which he drew on the so-called “Map of the Land from the Seho Era.” The Tokugawa shogunate confirmed the Matsumae clan's claims to the island in 1715, although no actual incursion by the Japanese was observed during this period. Apparently, even the Ainu likely did not live on the island year-round, but only visited it from Sakhalin, Hokkaido, and Kunashir to hunt marine mammals. In 1719, Peter I sent an expedition led by Ivan Evreinov and Fyodor Lushin to Kamchatka, which reached as far south as Simushir.

By 1734, all indigenous Ainu had adopted Christianity and were gradually Russified.