The cathedral was originally founded by the Society of Jesus. They set up the Immaculate Conception Mission (French: Mission de L’Immaculée Conception) for the Fort William First Nation. In July 1849 two French Jesuit missionaries, Fr Pierre Choné (1808-1879) and Fr Nicolas Frémiot (1818-1854) came to the area and started the mission.
The foundation stone was laid on 10 October 1891, and the first Mass was celebrated on 21 August 1892. The Jesuit parish priests made plans for the construction of an elementary school later that decade.
In Autumn 1924, the Jesuits handed over administration of the parish to the Diocese of Sault Sainte Marie.
In 1952, the Diocese of Fort William was created and St. Patrick's became its cathedral. In 1970, the diocese was renamed and it became the Diocese of Thunder Bay. From 1955, plans were drawn up to build a new larger cathedral. Three plots of adjacent land was purchased for a total of $50,000.
In September 1962, the old church was demolished. A year later, 15 September 1963, the foundation stone of the new cathedral was laid and a year after that, on 8 September 1964, the first Mass was celebrated.
In 2004, the new Holy Family Garden Shrine was built on the southern side of the Cathedral Grounds and the Chapel of Our Lady was remodeled. The Cathedral also owns the park across the street, which is maintained by the City of Thunder Bay.