In 1817, Hughes came to the United States. He settled in Chambersburg, PA, where his father had emigrated a year earlier. He attempted to attend Mount St. Mary's College in Maryland, with out success on his own. He was eventually was hired by Fr. John Dubois as a gardener. During this period he befriended and impressed Mother Elizabeth Ann Seton who convinced Dubois to assist Hughes's application to Mount St. Mary's. Hughes was admitted to Mount St. Mary's in September 1820, as a regular student.
In October, 1826, Hughes was ordained to the priesthood by Bishop Henry Conwell, of the Diocese of Philadelphia, to which Hughes had attached himself.
After attending to a number of posts in the Philadelphia Diocese, as well as at St. Mary's, he was consecrated bishop on January 7, 1838 with the titular see of Basileopolis. On December 20, 1842, Hughes was named Bishop of the Diocese of New York, and when the diocese was elevated to the status of archdiocese, on July 19, 1850, he became the first Archbishop of New York.
Among the various causes championed by Hughes, his influence is felt especially in the realm of higher education. He founded Manhattan College, St. John's College (now Fordham University0, Fordham Prep, the Academy of Mount St. Vincent (not the College of Mount Saint Vincent), and Marymount College. He also oversaw the start of construction of The Cathedral of St. Patrick on Fifth Avenue.
Archbishop Hughes died on January 3, 1864, and was buried at The Basilica of Saint Patrick's Old Cathedral, (also known as Old St. Patrick's) on Mulberry Street below Houston Street. His remains were then exhumed in 1883, and interred in the crypt under the alter of the new cathedral