Zelada was appointed titular Archbishop of Petra on 23 December 1766, and cardinal priest in the consistory of 19 April 1773.

Appointed by means of a papal brief of Pope Clement XIV, he was the principal negotiator for the Holy See and composer of the brief Dominus ac Redemptor of 8 June 1773, that suppressed the Society of Jesus.

On 2 October, the Diario di Roma reported he had been given a Meissen group representing the death of St. Francis Xavier, confiscated from the Jesuits.

[5] Already Camerlengo of the Sacred College of Cardinals (1783–84), his career culminated in his appointment by Pope Pius VI as Cardinal Secretary of State, 1789–1796, in which post he was entrusted with difficult negotiations with the French Revolutionary state, which included his conclusion of peace in 1793.

Librarian of the Holy Roman Church from 15 December 1779 until his death, Cardinal Zelada was not known for his religious fervor.