Following the death of Enrico Manfredini, Biffi was named Archbishop of Bologna on 19 April 1984 and installed on the following 1 June. He was elected President of the Episcopal Conference of Emilia-Romagna on 7 July 1984. Pope John Paul II created him Cardinal-Priest of Santi Giovanni Evangelista e Petronio in the consistory of 25 May 1985. Biffi preached the Lent spiritual exercises for the pope and Roman Curia in 1989. He retired from the governance of the archdiocese in December 2003 and was succeeded by Carlo Caffarra.