Stefano Nardini was born in Forlì.^[1] He received a doctorate of both laws.^[1]

As a young man, Nardini served in the military, before joining the ecclesiastical estate and traveling to Rome.^[1] He became a canon of Ferrara Cathedral, and later General Treasurer of the Marche.^[1] During the pontificate of Pope Callixtus III, he was governor of Romagna.^[1] Under Pope Pius II, he was a referendary, and later, a protonotary apostolic.^[1] He then served as Pius II's nuncio to Germany; the pope wrote to him on 15 July 1459 about the advance of the Ottoman Empire in the Kingdom of Bosnia.^[1]

On 13 November 1461 he was elected Archbishop of Milan. He occupied that see until his death.^[1] He then served as a nuncio in the Kingdom of Aragon, in which capacity he successfully sought the derogation of a pragmatic sanction that endangered the freedom of the church.^[1] In July and August 1464, he accompanied the pope to Ancona.^[1]

Following the death of Pope Pius II, he returned to Rome for the papal conclave of 1464 that elected Pope Paul II.^[1] During that conclave, the College of Cardinals had agreed that the number of cardinals should be fixed at 24; Archbishop Nardini and Teodoro Lelio, Bishop of Treviso, advised the new pope in September 1464 not to agree to this limitation.^[1] Paul II named Nardini nuncio extraordinary to the Kingdom of Naples.^[1] From April 1467 to June 1468, he resided in Paris as papal legate to the Kingdom of France.^[1] He was present in Rome when Paul II died in July 1471 and the College of Cardinals named him temporary governor of Rome.^[1] In the papal conclave of 1471, the College of Cardinals elected Pope Sixtus IV as the new pope.^[1]

In the consistory of 7 May1473, Sixtus IV made Nardini a cardinal priest; he received the red hat and the titulus of Sant'Adriano al Foro (a deaconry elevated pro illa vice to titulus).^[1]

As cardinal, he built the Palazzo Nardini on the Via del Governo Vecchio, next to the Palazzo Taverna.^[1] On 10 June 1476 he accompanied the pope to Viterbo, and later to Foligno, because of an outbreak of bubonic plague in Rome.^[1] In 1476, he opted for the titulus of Santa Maria in Trastevere.^[1] He was Camerlengo of the Sacred College of Cardinals from 8 January 1481 until 7 January 1482.^[1] In 1483, he founded the Collegio Nardini.^[1]

He participated in the papal conclave of 1484 that elected Pope Innocent VIII.^[1] The new pope named him legate to Avignon, but he died before he could perform his legation.^[1]

He died in Rome on 22 October 1484.^[1] He is buried in St. Peter's Basilica.^[1]