The Dicastery for the Clergy was first set up as the Sacra Congregatio Cardinalium pro executione et interpretatione concilii Tridentini interpretum by Pope Pius IV in the apostolic constitution Alias Nos of 2 August 1564 to oversee the proper application and observation of the disciplinary decrees of the Council of Trent throughout the Catholic Church.

By 2009, Pope Benedict XVI made the Congregation responsible for managing the guidelines concerning clergy who maintained their clerical status after violating their vows of celibacy.

[2] In January 2013, the motu proprio Fides per doctrinam transferred the competency on catechesis from the Congregation for the Clergy to the Pontifical Council for the Promotion of the New Evangelisation.

He said that "In such cases there are, unfortunately, Bishops and Superiors who think that, after having provided economically for the children, or after having transferred the priest, the cleric could continue to exercise the ministry.

[3] On 3 June 2021, Pope Francis tasked Egidio Miragoli, Bishop of Mondovì, with conducting a review of the Congregation in anticipation of the replacement of its prefect in August.