Born into a Catholic family during the Penal Laws, the Hughes family would have experienced great difficulty in their native Ireland. In 1816, Hughes they emigrated to America where they eventually settled in Chambersburg, Pennsylvania.
Hughes felt a calling to the priesthood and was ordained on the 15th of October 1826 by Bishop Henry Conwell. His first placement was as curate of St Augustine's Church in Philadelphia. He was also sent as a missionary to convert Protestants in smaller towns in Pennsylvania. His career in the church continued in an upward trajectory as he served in a number of churches and even founded a home for orphans. He was also involved in debates on whether or not the Catholic faith was truly compatible with the ideals of American Republicanism during which he staunchly defended the position of the church.
On the 7th of August 1837, Hughes was chosen by Pope Gregory XVI to be the coadjutor bishop of the Diocese of New York. When the bishop under whom he served died on the 20th of December 1842, Hughes naturally stepped into the role of Bishop. This was at a time of anti-Catholic riots in New York. Hughes spoke out against the treatment of Catholics and campaigned for more equality, particularly in the schools systems.
In 1850, the diocese of New York became an Archdiocese, which meant that, on the 19th of July 1850, Hughes became the very first Archbishop of New York. This position won him the great privilege of becoming Lincoln's special envoy to The Vatican.
Hughes served in this role of Archbishop until his death on the 3rd of January 1864. He was buried in the old St Patrick's Cathedral, but when the new cathedral was built, his remains were exhumed and reinterred under the altar of the new building.