Prefontaine was born in 1838 in Longueuil, Quebec, near Montreal, the eldest of five children in a devout French-speaking Catholic family. He studied at parochial schools and Nicolet College before entering the Grand Seminary of Montreal in 1859. His ordination came on November 20, 1863, and his departure followed almost immediately. The Pacific Northwest was mission territory, sparsely settled and desperately short of Catholic clergy. The journey via Panama was long and uncertain, but Prefontaine made it to Vancouver, where he studied English and Chinook Jargon, the pidgin trade language that served as a lingua franca among the region's diverse populations. Learning Chinook was practical: the territory's inhabitants included Indigenous peoples, fur traders, and settlers from a dozen countries, and a priest who could speak only French would reach very few of them.

Prefontaine arrived in Seattle and rented a small two-room house at Third Avenue and Yesler Way for six dollars a month. One room became his living quarters; the other became a chapel where he conducted services while raising funds to build a proper church. The location placed him at the heart of early Seattle, near the sawmill that Henry Yesler had built on the waterfront and the skid road that gave the surrounding neighborhood its character. From this modest beginning, Prefontaine built the city's first Catholic church and spent the next four decades serving Seattle's growing Catholic community. He witnessed the city burn in the Great Seattle Fire of 1889 and watched it rebuild. He saw the population swell during the Klondike Gold Rush. Through all of it, the French Canadian priest who had arrived speaking no English became a fixture of the city's civic and spiritual life.

In July 1908, Pope Pius X conferred on Prefontaine the honorary degree of protonotary apostolic, a recognition of his distinguished service in Seattle since 1869. Bishop Edward John O'Dea invested Prefontaine with the robes and title of Monsignor, making him a Member of the Papal Household. The honor acknowledged nearly forty years of continuous ministry in a city that had grown from a frontier settlement into a major Pacific port. Prefontaine was seventy years old, and the recognition from Rome came less than a year before his death in 1909. He had never returned to Quebec.

Prefontaine's will contained a bequest of five thousand dollars to the city of Seattle "for a fountain in a public square." The fountain was not completed until 1925, sixteen years after his death, but it stands today at the intersection of Third Avenue and Yesler Way, approximately where his first rented house and improvised chapel once stood. A short street nearby, Prefontaine Place South, marks the site of his first church. On that street stands the Prefontaine Building, a nearly triangular six-sided structure in the Beaux-Arts style completed in 1909, the year of his death. These modest namesakes cluster within a few blocks of Pioneer Square, small traces of a man who crossed a continent and an ocean to minister to a town that barely existed when he arrived. The fountain, the street, and the building form an accidental memorial to the quiet persistence that built Seattle's spiritual foundations one rented room at a time.