A native of Montreal, Prendergast was born in 1944, one of five children. He entered the Jesuit novitiate in 1961 and was ordained a priest in 1972. He holds a Bachelor of Arts degree from Fordham University, as well as the Master of Divinity and Doctor of Theology degrees from Saint Mary's University, Halifax through its earlier affiliation with Regis College, now part of the Toronto School of Theology.
For his period of Regency, Prendergast taught Latin and Greek at Loyola High School in Montreal from 1967-1969 and, after ordination and graduate studies in theology, taught in Halifax at the Atlantic School of Theology from 1975–1981, then was Rector of Toronto's Regis College from 1981–87, and its Dean of Theology from 1991-1994. From 1992-94 he assisted Frederick Henry, then the Auxiliary Bishop of London (Ontario), later Bishop of Thunder Bay and Bishop of Calgary, in conducting an apostolic visitation of the English-language seminaries in Canada for the Vatican. In 1995, he was a Visiting Professor at the Ecole Biblique in Jerusalem.
Pope John Paul II named Prendergast the Titular Bishop of Slebte and an Auxiliary Bishop of the Archdiocese of Toronto on February 22, 1995, He was consecrated in St. Michael's Cathedral on April 25, 1995. In Toronto, his duties as auxiliary included responsibility for the Western Pastoral Region (Etobicoke, part of North York and the region of Peel-Dufferin), liaison with the theological faculties and planning the preparations for the Great Jubilee.
In 1998 Prendergast was appointed the Archbishop of Halifax, and installed on September 14, 1998. As such, he served ex officio as the Chancellor of Saint Mary's University, Halifax, a position granted to the Archbishop of Halifax until 2007, when the archdiocese and the university agreed to instead bestow the title of Visitor.
Prendergast was named as the ninth Archbishop of Ottawa by Pope Benedict XVI on 14 May 2007 and was installed on June 26, 2007. In this office, he also serves ex officio as Chancellor of Saint Paul University.
After serving on the Canadian Bishops' Commission for Relations with Associations of Clergy, Consecrated Life and Laity, as a member of the CCCB Theology Commission [now known as the Doctrine Commission], its Commission on Social Communications, several terms on the Permanent Council (including since 2015 as representative of the Bishops of Ontario) and earlier as co-chair of the national Anglican-Roman Catholic dialogue, Archbishop Prendergast is, since October 2014, a member of the CCCB's Episcopal Liaison Committee to the Canadian Catholic Organization for Development and Peace.
His other responsibilities include president of National Evangelization Teams Canada (NET Canada) and chair of CNEWA (Catholic Near East Welfare Association) Canada, both of which are based in Ottawa. Aside from other pastoral involvements, Bishop Prendergast is a teacher, writer and retreat giver. From 1994 to 2005, he wrote a weekly Scripture column in the Catholic Register, a collection of which was edited and published as Living God's Word: Reflections on the Sunday Readings for Year A, B, C by Novalis [Toronto: 2010-2012/reprinted Mumbai: St Paul Publications, 2013]; he has been a writer or editor for several journals, and lectured and given retreats across Canada, in the U.S. and Rome.
Prendergast was Apostolic Administrator of the Diocese of Yarmouth, Nova Scotia (now part of the Halifax-Yarmouth Archdiocese) from January 2002 to May 2007, took part in the Apostolic visitation to Ireland which began in 2010 and was completed in 2011 and, since January 13, 2016, is serving as the Apostolic Administrator of the Diocese of Alexandria-Cornwall (Ontario) .