He was ordained a priest on 4 September 1960 and taught at the seminary of Saint Mary’s and the secondary school in Chadiza. He worked in the diocesan office for vocations.
He was appointed bishop on 11 November 1970 and was consecrated on 7 February 1971.
On 30 November 1996 he was appointed Archbishop of Lusaka and held this position until 28 October 2006. He is Zambia’s first cardinal.
He served as president of the Zambia Episcopal Conference (1972-1975; 1988-1990; 1999-2002). He was also president of the Association of Member Episcopal Conferences in Eastern Africa (AMECEA) from 1979 to 1986. On 3 September 1984, while serving this conference, he inaugurated the Catholic University of Eastern Africa in Nairobi, Kenya.
He has been tied closely to the growth of the Church in Africa and campaigned for the cancellation of the international debt of the poorest of countries.
Created and proclaimed Cardinal by Benedict XVI in the consistory of 20 November 2010, of the Title of Santa Emerenziana a Tor Fiorenza (Saint Emerentiana at Tor Fiorenza).
Cardinal Joseph Medardo Mazombwe died on 29 August 2013.