Zuppi was born on 11 October 1955 in Rome. He studied at the seminary in Palestrina and earned his degree in theology at the Pontifical Lateran University in Rome. He earned a doctorate at the Sapienza University of Rome, writing his thesis on the history of Christianity. He was ordained a priest on 9 May 1981. He worked with the Community of Sant'Egidio, a Catholic lay association devoted to ecumenism and conflict resolution. He participated with several colleagues in negotiations that helped end the civil war in Mozambique in 1992 and was made an honorary citizen of that country. On 31 January 2012, Pope Benedict XVI named him an Auxiliary Bishop of the Diocese of Rome and titular bishop of Villa Nova. He was ordained a bishop on 14 April 2012 by Cardinal Agostino Vallini, Vicar General of the Diocese of Rome. He was the auxiliary responsible for the city center, including the Trastevere neighborhood where Sant'Egidio is headquartered. There he led efforts to improve care for the poor and the elderly and developed outreach programs for drug addicts and gypsies. He also established relations with traditionalists and celebrated a Pontifical Mass according to the Tridentine rite. Pope Francis appointed him Archbishop of Bologna on 27 October 2015. In May 2018, he contributed an essay to the Italian translation of James Martin's Building a Bridge, Un ponte da costruire. He wrote that it was "useful for encouraging dialogue, as well as reciprocal knowledge and understanding, in view of a new pastoral attitude that we must seek together with our L.G.B.T. brothers and sisters" and that it will "help L.G.B.T. Catholics feel more at home in what is, after all, their church". On 1 September 2019 Pope Francis announced that he plans to create Zuppi a cardinal on 5 October; he was the first head of an Italian see traditionally headed by a cardinal to be named a cardinal by Francis. On 5 October 2019, Pope Francis made him Cardinal Priest of Sant'Egidio. He was made a member of the Dicastery for Promoting Integral Human Development on 21 February 2020, and a member of the Administration of the Patrimony of the Apostolic See on 18 April 2020.
