Although it had missionary beginnings as early as 1724, the Catholic faith was not formalized in Key West until the construction of the first Catholic church in 1852. Located on Duval Street and dedicated under the title St. Mary Star of the Sea, it was the first Catholic parish established in South Florida. It is the third oldest Catholic parish in all of Florida. Destroyed by fire in 1901, it was replaced in 1905 by the present basilica on Truman Avenue, which was the first non-wooden place of Catholic worship in South Florida.
Yellow fever took its toll on the diocesan priests and there was a shortage of local vocations. Therefore Bishop John Moore of the Diocese of St. Augustine offered the missions of South Florida to the Jesuits of New Orleans. St. Mary Star of the Sea became a Jesuit parish in 1898 and remained so until 1970.
The spiritual and historical significance of the parish throughout the last two centuries along with the architectural beauty and uniqueness of the church was recognized by Archbishop Thomas Wenski, who petitioned the Vatican for the designation of minor basilica. On February 11, 2012, St. Mary Star of the Sea was honored with the title of Minor Basilica, the fifth in the State of Florida. The formal dedication was held May 31, 2012.