He was born on 31 December 1947, in Finthen, a suburb of Mainz to Martin Müller, an employee of a car-manufacturing firm, and his wife Lioba née Straub. He attended the local school, Willigis Gymnasium and studied philosophy and theology in Mainz, and later in Munich and Freiburg im Breisgau. He earned his doctorate in 1977 under Professor, later Cardinal, Karl Lehmann on the subject of „The Church and Sacraments in Religionless Christendom. Bonhoeffer’s Contribution to an Ecumenical Sacramental Theology” („Kirche und Sakramente im religionslosen Christentum. Bonhoeffers Beitrag zu einer ökumenischen Sakramententheologie”). 

Since 1990, he has been a member of the Commission for Doctrine and Faith of the German Bishops’ Conference, and was also a member of the International Theological Commission from 1998 to 2003. In 1999 he was appointed as peritus (theological consultant) to the Vatican’s Synod of European Bishops. In 2001 he was a theological consultant to the International Bishops’ Synod in Rome on the subject of „The Bishop as Servant of the Gospel of Jesus Christ for World Hope.” 

On 11 February 1978 he was ordained as a priest in Mainz-Finthen by Cardinal Volk. He subsequently served in three parishes (Klein-Krotzenburg, Bürstadt-St. Michael, Offenbach-St. Josef) and as religious education teacher at secondary schools in Büdingen and Nidda. He qualified as professor in 1985 in Freiburg im Breisgau and the following year took up the Chair of Dogmatic theology at the Ludwig-Maximilian University in Munich, where he continues to be an honorary professor. 

During his career as a university professor (1986-2002) in the Capital of Bavaria–and a visiting professor in numerous other institutions–he provided pastoral assistance to the Parish of Leiden Christi in Munich.

On 1 October 2002, Pope John Paul II nominated him Bishop of Regensburg.  He was consecrated Bishop by the then Archbishop of Munich and Freising, Cardinal Friedrich Wetter in Regensburg Cathedral on 24 November 2002, the Feast of Christ the King. The principal consecrator was the then Archbishop of Munich and Freising, Cardinal Friedrich Wetter. Also present was the then Prefect of the Congregation for the Doctrine of the Faith, Cardinal Joseph Ratzinger. Bishop Müller chose „Dominus Jesus” as his episcopal motto. 

Preaching, the promotion of culture, sacred liturgy, and the charitable works of the Church have been amongst the priorities of his episcopal ministry. In November 2003, he set up a church school trust that has taken on the sponsorship of nine church schools to date. Between 2004 and 2005, he undertook the pastoral visitation of the eight regions of his diocese. In 2005, he reorganized the diocesan lay apostolate in order to make the structures more efficient and more in conformity with Canon Law. He also initiated and lent his support to the „Inner City Counselling” („Innenstadtseelsorge”) project in the centre of Regensburg in order to address the diverse counselling needs of residents of the city centre and tourists. On his initiative, between 2008 and 2009, the city parishes of Regensburg implemented a city mission involving over 1000 voluntary helpers, with the objective of stimulating dialogue and making the Christian faith a topic for discussion again. He also revived the 600 year old Kötzting Pentecostal Ride (Kötztinger Pfingstritt) establishing it as Eucharistic procession, which attracts 40,000 people every year.

During his episcopate in Regensburg, he participated in the 2005 Synod of Bishops, on the Eucharist, and welcomed Pope Benedict XVI during his apostolic visit in Bavaria in September 2006. 

Pope Benedict XVI personally entrusted him with the publication of his „Collected Writings” and asked him to oversee the publication of his „Complete Works” by Herder’s of Freiburg. In order to further this undertaking, which comprises 16 volumes, in 2008 the then Bishop Müller founded the Pope Benedict XVI Institute in Regensburg. The principle task of this institute is to collect and publish the works of Joseph Ratzinger in their entirety, including previously unedited writings. 

On 12 June 2012 Pope Benedict nominated him a member of the Congregation for Catholic Education and the Pontifical Council for the Promotion of Christian Unity. These nominations were reconfirmed in 2014 by Pope Francis. On 2 July 2012 Pope Benedict, following the retirement of Cardinal William Levada, nominated him Prefect of the Congregation for the Doctrine of the Faith and President of the Pontifical Commission “Ecclesia Dei”, the International Theological Commission and the Pontifical Biblical Commission, raising him to the dignity of Archbishop.  The following 29 September, he became a member of the Pontifical Council for Legislative Texts. On 21 September 2013, Pope Francis confirmed him as Prefect of the Congregation for the Doctrine of the Faith and the following year nominated him among the members of the Congregation for the Eastern Churches, the Congregation for Institutes of Consecrated Life and Societies of Apostolic Life and the Pontifical Council for Culture. He was the Prefect of the Congregation for the Doctrine of the Faith until 1 July 2017.

He was created Cardinal by Pope Francis in the consistory of 22 February 2014 and is Cardinal Deacon of the Church of Sant’Agnese in Agone, Rome.

Pope Francis appointed him a member of the Apostolic Signatura on 21 June 21 2021.

He has received numerous international accolades. Amongst other honors, in 2001 he became a member of the Pontifical Academy of St. Thomas Aquinas and, in 2002, was made a correspondent member of the Theological section of the Real Accademia de doctores de España in Madrid. He has been granted the title Dottore Honoris Causa by three Polish Catholic universities (Lublin 2004, Varsavia 2007 and Breslavia 2015) and, for his collaboration with the theologian Gustavo Gutiérrez, the University of Lima in Peru also granted him an honorary doctorate.

Cardinal Müller has published in many fields, including ecumenism, modern theology, the theology of revelation, theological hermeneutics and ecclesiology.  To date he has more than 500 academic publications. Amongst the most widely known are his Katholische Dogmatik Für Studium und Praxis der Theologie published by Herder (English translation forthcoming).