The parish of St. Anthony was established in 1903 by Bishop Michael A. Tierney in response to a surge of Italian immigration in the Hill section of New Haven. Appointed founding pastor was Scalabrini Father Bartolomeo Marenchino, C.S. He came to St. Anthony in 1904 from St. Michael Parish, where St. Anthony parishioners had worshiped before the new parish was founded. Some 600 to 700 families made up the new congregation. Mostly laborers, craftsmen and shopkeepers, they melded powerful memories of their heritage and visions of the future into the "love story of a dynamic Italian Catholic congregation." Among the pioneering parish trustees were Angelo Porto and Santo Compasso. Prominent New Haven Italians like Paul Russo and William F. Verdi also helped organize the launching of the parish. A house was purchased on Gold Street to serve as the first rectory.

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At the corner of Gold Street and Washington Avenue, a beautiful church of Vernacular Renaissance design was dedicated by Bishop Tierney on March 5, 1905. It featured an unusually rounded nave as well as a bell donated by nationally known theater magnate S. Z. Poli of New Haven. A people of history and culture, parishioners donated dozens of imported statues with uniquely crafted crystal eyes to remind them of their familiar Italian saints. In 1918, a new rectory was constructed.

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About 12,000 baptisms had taken place during Father Marenchino's tenure by the time his successor, Father Silvio Sartori, C.S., arrived in June 1925. The next parish project was construction of a school. On August 30, 1936, Bishop Maurice F. McAuliffe dedicated St. Anthony School on Gold Street, complete with medical clinic. The school, serving 300 pupils, was staffed by the Missionary Zealatrices of the Sacred Heart, who took up residence at St. Anthony's Home for Orphans. Depressed times and an exodus of parishioners to the suburbs closed St. Anthony-School in 1971. 

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The church was rededicated in 1975. Its basement shrine to St. Anthony became a focal point for the revival of traditional piety, which sparked a cultural renaissance. Including a blessing of the sick, St. Anthony's feast became a three-day festival.

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On September 16, 2009, the nearby parish of Sacred Heart was closed because of the declined condition of the church and rectory buildings. By indication of Archbishop Henry Mansell, the parish community of Sacred Heart was transferred to St. Anthony where both congregations shared the space and the responsibilities of the one church campus. In 2017, the communities were merged into one St. Anthony Parish and is home to a diverse community.