Evidence of human habitation in Mie dates back more than 10,000 years. During the Jōmon and Yayoi periods, agricultural communities began to form along the river and coastal areas of the region. Ise Shrine is said to have been established during the Yayoi period, and in the 7th century the Saikū Imperial Residence was built in what is now Meiwa Town to serve as both a residence and administrative centre for the Saiō, an Imperial Princess who served as High Priestess of Ise Shrine.
During the Edo period, the area now known as Mie Prefecture consisted of several feudal domains, each ruled by an appointed lord. Transport networks, including the Tokaido and Ise Roads, were built. Port towns such as Ohminato, Kuwana and Anōtsu, posting stations and castle towns flourished. Pilgrimages to Ise Shrine also became very popular.
After the Meiji Restoration, the former provinces of Ise, Shima and Iga as well as a portion of eastern Kii, were organized and reorganized repeatedly. In 1871 the area from the Kiso Three Rivers in the north to present-day Tsu became Anōtsu Prefecture, and the area south of that became Watarai Prefecture. In 1872, the Anōtsu prefectural seat moved from Tsu to Yokkaichi, and the prefecture itself was renamed Mie. For a variety of reasons, including the strong likelihood that Mie would eventually merge with Watarai, the prefectural seat returned to Tsu the following year, and Mie Prefecture took its present-day form in 1876, when it merged with its southern neighbor.
The name Mie supposedly was taken from a comment about the region made by Yamato Takeru on his way back from conquering the eastern regions.
In 1959 many lives were lost as parts of Mie were devastated by the Ise-wan Typhoon, the strongest typhoon to hit Japan in recorded history. Crops were destroyed, sea walls ruined, roads and railways damaged and a substantial number of people were injured or left homeless.