Minusinsk marks the center of the Minusinsk Depression, probably the most important archaeological area north of Pazyryk. It is associated with the Afanasevo culture, Tashtyk culture, and Tagar culture - all of them named after settlements in the vicinity of Minusinsk.
The Russian settlement of Minyusinskoye (Минюсинское) was founded in 1739, at the confluence of the Minusa River with the Yenisei. Turkic Min Usa means "my brook" (or "thousand rivers" ). The spelling was changed to Minusinskoye (Минусинское) in 1810.
By 1822, the settlement had emerged as a regional center of farming and transit trade and was incorporated as the town of Minusinsk. During the 19th century, it was a node of cultural activities for a very large area. The Martyanov Natural History Museum was opened there in 1877.
The town was also a place of political exile. Vladimir Lenin used to visit Minusinsk on numerous occasions when he was in exile in the nearby village of Shushenskoye between 1897 and 1900. During the Russian Civil War, Minusinsk was the setting of the Minusinsk Rebellion (1918).