From May 2005 until June 2012, he served as Prefect of the Congregation for the Doctrine of the Faith under Pope Benedict XVI; he was the highest ranking American in the Roman Curia.

[2] From 1976 to 1982, Levada was an official of the Congregation for the Doctrine of the Faith (CDF) in the Vatican, having been recommended by Cardinal Joseph Bernardin.

[2] In 1982, Cardinal Timothy Manning, Archbishop of Los Angeles, named Levada as the executive director of the California Catholic Conference of Bishops which has its offices in Sacramento.

In November 2003, Levada was appointed as chairman of the United States Conference of Catholic Bishops Committee on Doctrine.

[2] On September 18, 1998, he was principal consecrator at the episcopal ordination of Monsignor John C. Wester as an auxiliary bishop of San Francisco.

[2] As Archbishop of San Francisco, Levada also served as grand prior of the Northwest Lieutenancy (USA) of the Equestrian Order of the Holy Sepulchre of Jerusalem, and as conventual chaplain for the Western Association (USA) of the Sovereign Military Hospitaller Order of St. John of Jerusalem of Rhodes and of Malta.

[11][12] In 1985, as a contact of Boston's Cardinal Law about the issue, Levada was given a report by a three-man panel headed by Father Tom Doyle about medical, legal, and moral issues posed by abusive clerics in an attempt to present the report to the U.S. Conference of Catholic Bishops at their June 1985 meeting.

"[14] As archbishop in Portland, Levada removed Father Joseph Baccellieri, a parish priest accused of child molestation, in 1992 but did not refer the matter to the police.

[15] After spending $53 million to settle more than 100 claims of priestly sex abuse, Portland in 2004 became the first U.S. Roman Catholic archdiocese to declare bankruptcy.

[22] Cardinal Levada, who was already a member of the Pontifical Commission Ecclesia Dei, the organ of the Holy See charged with seeking the reconciliation of the Society of St. Pius X and similar groups with Rome and regulating celebration of the Sacraments according to the 1962 texts in Latin, was appointed its president on July 8, 2009,[23] in accordance with Pope Benedict XVI's motu proprio Ecclesiae Unitatem, which makes the Prefect of the Congregation for the Doctrine of the Faith ex officio head of the Ecclesia Dei Commission.

Cardinal Levada, as president of the Pontifical Commission Ecclesia Dei signed the document which was approved by Pope Benedict XVI on April 8 and is dated April 30, the memorial of Pope Pius V. The instruction also contains within it the fruits of the triennial examination of the application of the law, which had been planned from the outset.

On October 20, 2009, Cardinal Levada and Archbishop Joseph DiNoia held a press conference in which they announced that Pope Benedict was preparing to release an apostolic constitution that was later presented under the title Anglicanorum coetibus that would allow Anglicans, both laity and clergy, to join the Catholic Church and maintain their corporate identity.

"[26] The press release envisaged that married Anglican clergy who join the Catholic Church will be ordained to the priesthood, but excluded ordination to the episcopate: "Historical and ecumenical reasons preclude the ordination of married men as bishops in both the Catholic and Eastern Orthodox Churches.

[27] On October 31, 2009, Cardinal Levada responded to speculation that the rule whereby in some Eastern Catholic Churches ordination to the diaconate and priesthood is open to married men as well as to celibates will apply also to the personal ordinariates for former Anglicans.

Objective criteria for circumstances in which a dispensation from celibacy may be requested will be worked out jointly by the personal ordinariate and the episcopal conference.

Two months later, Levada publicly reiterated this and singled out Catholic politicians who legislated to allow abortion: "The individual politician, like any Catholic, who is at odds with the teaching of the Church about the principle involved, i.e., that abortion constitutes the killing of innocent human life and is always gravely immoral has an obligation to reflect more deeply on the issue, in the hope of allowing the persuasive character of this infallibly taught teaching to become part of his belief and value system.

Levada objected that this violated Catholic teaching on the unique status of marriage, and circumvented the provisions by stating that unmarried employees of the archdiocese could designate any person sharing the same address as their beneficiary – which meant complying with the statute while in Levada's view avoiding a privileged status for unmarried domestic partnerships.

[31] Levada led a march of approximately 1,000 people through the streets of San Francisco in April 2005 to protest against same sex marriage.

[32] In 2006, Levada stated that the Archdiocese of San Francisco should more carefully avoid allowing gay couples to adopt children locally.

...The variabilities which marked the human process of its discovery and formulation made such particular applications inherently unsuited to be considered for infallible definition.

...For such formulations must remain essentially open to modification and reformulation based upon moral values as they are perceived in relation to the data and the experience which mark man's understanding of himself.

According to rabbi David Rosen, Levada made it clear that there was intrinsic value in conducting interfaith dialogue with Jews even without any ulterior motives of proselytizing.

"[39] In 1999, some Traditionalist Catholics complained about Levada's refusal to grant the indult for Tridentine Masses to be celebrated publicly in his archdiocese; they said that this was against Pope John Paul II's motu proprio Ecclesia Dei.

[42][44] After pleading no contest on January 25, 2016, he was ordered to pay a fine and fees totalling $462 and had his driving license revoked for one year.