He was ordained a priest on 25 July 1914 by Archbishop Ildefonso Pisani, and four months later, in November, travelled to Rome to study at the Pontifical Biblical Institute.

Although he had been seen by Vatican watchers ever since 1953 as a possible successor to Pius XII and was listed by l'Osservatore Romano as a papabile, his reputation as the most idiosyncratic of all the cardinals and the desire for a transitional pontiff saw him passed over in favor of Roncalli in 1958.

A friend of the Freemason and piduist Umberto Ortolani, who had grown up economically and politically in Bologna, he was one of the first members of the Catholic hierarchy to establish a dialogue with the Communists.

On 12 February 1968, Cardinal Lercaro was forced to step down from his position as Archbishop of Bologna and in 1971, he lost his right to participate in any future conclave upon reaching the age of eighty according to the then-recent motu proprio Ingravescentem aetatem.

At one point during World War II, Lercaro was forced to operate under the alias of "Father Lorenzo Gusmini" and live in a vacant monastery cell to avoid being killed by Nazi collaborators.