He was appointed Bishop of Nha Trang on 13 April 1967 and consecrated on 24 June. On 24 April 1975 Pope Paul VI promoted him to Coadjutor Archbishop of Saigon, now Ho Chi Minh City, but with the arrival of the communist regime he was arrested and imprisoned on 15 August. Without ever being tried or sentenced, he spent 13 years in prison, nine of them in solitary confinement, until his release on 21 November 1988. Many of his ancestors had given their lives for the Catholic faith as victims of persecution between 1698 and 1885.

On 24 November 1994 he was appointed Vice-President of the Pontifical Council for Justice and Peace. Since 24 June 1998 he has been President of the same Council.

Created and proclaimed Cardinal by John Paul II in the consistory of 21 February 2001. Diaconate of Holy Mary of the Stairs.

Cardinal François Xavier Nguyên Van Thuân died on 16 September 2002.