During the Edo period, all of Kai Province was tenryō territory under direct control of the Tokugawa shogunate, although the portion around modern day Ōtsuki was part of the short-lived Tamimura Domain, which was suppressed in 1704. Also during the Edo period, the Kōshū Kaidō, one of the Edo Five Routes, passed through Ōtsuki, which with 12 of the 45 post stations has more post stations than any other municipality in Japan. The eleven post stations spread from Shimotorisawa-shuku to Kuronoda-shuku.
During the cadastral reform of the early Meiji period in July 1, 1889, the village of Hirosato was created within Kitatsuru District, Yamanashi Prefecture. On April 1, 1933 the village was raised to town status, and renamed Ōtsuki. The town was bombed by the United States on August 13, 1945, only two days before the end of World War II. The town was elevated to city status on August 8, 1954.