Pignedoli received episcopal consecration on 11 February 1951 from Cardinal Adeodato Giovanni Piazza, OCD, with Archbishop Valerio Valeri and Bishop Beniamino Socche serving as co-consecrators, in the Basilica of Saint Paul Outside the Walls.

On the following day, 6 March, he became the second President of the Secretariat for Non-Christians (later renamed the Pontifical Council for Interreligious Dialogue by Pope John Paul II on 28 June 1988).

[5] Pignedoli also established close friendships with Shōchō Hagami, a great acharya of Tendai Buddhism and one of the most prominent Japanese Buddhists of the 20th century, who played a leading role in promoting mutual respect and reconciliation among three monotheistic religions from an Asian side.

A towering figure in the Roman Catholic Church, cardinal Sergio Pignedoli was Pope Paul VI closest ally and confidant, and was widely expected to succeed him.

His main opponent was the conservative cardinal Giuseppe Siri of Genova, though since both of these legendary cardinals were unable to obtain a majority, a compromise candidate emerged, and Albino Luciani was elected as Pope John Paul I. Thirty three days later, following the sudden death of John Paul I, a second conclave convened in October 1978.

Pignedoli was again the leading contender for the papacy, but ultimately Karol Józef Wojtyła of Poland was elected as Pope John Paul II.