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It was in 1840 that the first settlers, most of whom came from Rivière-du-Loup, Saint-Arsène and Isle-Verte, settled on the territory of the future municipality. As early as 1842, a mission provided religious assistance to the few inhabitants, who founded a parish under the name of Saint-Épiphane in 1863, canonically erected in 1870.
In 1855, the municipality of Viger was officially created, named after Denis-Benjamin Viger (1774–1861). In 1873, Viger lost a small part of its territory for the creation of the municipality of Saint-François-Xavier (which would be dissolved in 1892). In 1894 Viger would change its name to the current Saint-Épiphane.
In 1950, Saint-Épiphane lost another small part of its territory when Saint-François-Xavier-de-Viger was created. In 1991, Saint-Épiphane updated its status from a parish municipality to become a regular municipality.
In the past, the Wolastoqiyik, Amerindians close to the Mi'kmaq, lived on a reserve near Saint-Épiphane.