After years as a Vatican diplomat, he served as Archbishop of Melbourne from 1967 to 1974, prefect of the Congregation for Divine Worship and the Discipline of the Sacraments from 1974 to 1981, and president of the Pontifical Council for the Family from 1981 until his death in 1983.

In September that year, Knox was transferred to the Pontifical Urban University in Rome, an institution belonging to the Congregation for the Evangelization of Peoples to train missionaries.

[1] Unable to return to Australia during World War II,[5] he remained in Rome and served as chaplain and vice-rector at the Pontifical Urban University.

Knox joined the Vatican diplomatic corps a staff member of the Secretariat of State in 1948, serving under Giovanni Battista Montini (later Pope Paul VI).

[6] On 20 July 1953, Knox was appointed Apostolic Delegate to British Africa and titular archbishop of Melitene by Pope Pius XII.

[1] He received his episcopal consecration on the following 8 November in Rome from Cardinal Celso Costantini, with Archbishops Filippo Bernardini and Antonio Samorè serving as co-consecrators.

During his tenure, he oversaw a significant expansion of the Catholic Church in India, including the creation of many new dioceses and the development of religious communities like the Missionaries of Charity founded by Mother Teresa.

On 13 April 1967, Knox was appointed to succeed Justin Simonds as the fifth Archbishop of Melbourne, despite the fact he had not lived in Australia for 30 years and had no direct pastoral experience.