Archbishop Gregory was ordained a Catholic Priest for the Archdiocese of Chicago on May 9, 1973. He was ordained a Bishop on December 13, 1983, after having served as an associate pastor at Our Lady of Perpetual Help Parish in Glenview, a member of the faculty at Saint Mary of the Lake Seminary in Mundelein, and a Master of Ceremonies to Cardinals Cody and Bernardin. Bishop Gregory was installed as the Seventh Bishop of Belleville on February 10, 1994 following ten years as Auxiliary Bishop of Chicago.

On November 13, 2001, Bishop Gregory was elected President of the United States Conference of Catholic Bishops, following three years as Vice President under Bishop Joseph Fiorenza of the Diocese of Galveston-Houston. Bishop Gregory served on the NCCB Executive and Administrative Committees, the Administrative Board, the Committee on Doctrine, and the United States Catholic Conference Committee on International Policy. He previously served as Chairman of the Bishops' Committees on Personnel (1998-2001), the Third Millennium/Jubilee Year 2000 (1998-2001), and Liturgy (1991-93).

Archbishop Gregory has written extensively on Church issues, including pastoral statements on the death penalty and euthanasia/physician-assisted suicide. He has published numerous articles on the subject of liturgy, particularly in the African-American community.

Archbishop Gregory was installed as the seventh Bishop, sixth Archbishop of Atlanta on January 17, 2005 at the Georgia International Convention Center in College Park, Georgia.