On January 4, 2000, Sartain was appointed the sixth Bishop of Little Rock, Arkansas, by Pope John Paul II. He received his episcopalconsecration on the following March 6 from Archbishop Eusebius J. Beltran, with Bishops J. Terry Steib and Andrew Joseph McDonald serving as co-consecrators. He was the first priest of the Diocese of Memphis to become a bishop. He selected as his episcopal motto: "Of You My Heart Has Spoken". Due to the increasing Hispanic population in Arkansas, Sartain took a course in Spanish in San Antonio, Texas, in 2001, and established Hispanic ministries throughout the state. He also ordained Arkansas's first Mexican-born priest and deacon. He worked to increase vocations; the diocese had ten seminarians and no ordinations in 2000, but fifteen seminarians and two ordinations in 2005. In 2005, he led more than 5,000 Catholics in a bilingual Eucharistic Congress. During his tenure, the Catholic population in Arkansas rose from 90,600 to over 107,000.
Bishop of Joliet
On May 16, 2006, Sartain was appointed as bishop of the Diocese of Joliet. He was installed on June 27, 2006, in the Cathedral of St. Raymond Nonnatus
Archbishop of Seattle
On September 16, 2010, he was appointed Metropolitan Archbishop of the Archdiocese of Seattle, succeeding Archbishop Alexander Joseph Brunett. He was installed as Archbishop on December 1, 2010 in St. James Cathedral in Seattle. On November 15, 2011, Sartain was elected Secretary of the United States Conference of Catholic Bishops ; he begins a three-year term in November 2012. His position also makes him chairman of the USCCB Committee on Priorities and Plans. In April 2012, Sartain urged parishes in the Seattle archdiocese to collect signatures to place Referendum 74 on the November ballot. The referendum sought to repeal Washington state's newly enacted same-sex marriage statute. "The word 'marriage' isn't simply a label that can be attached to different types of relationships," Sartain wrote. "Instead, 'marriage' reflects a deep reality – the reality of the unique, fruitful, lifelong union that is only possible between a man and a woman. There is nothing else like it, and it can't be defined or made into something that it isn't...Marriage can only be between a man and a woman because of its unique ends, purpose and place in society." On April 18, 2012, the Vatican announced the appointment of Archbishop Sartain to oversee a review of the Leadership Conference of Women Religious, a prominent umbrella group for nuns in the United States. It involved reviewing and changing the group's laws, programs and practices to correct practices that are "incompatible with the Catholic faith." On June 7, 2019, Sartain installed Paul D. Etienne, then Archbishop of Anchorage, as coadjutor archbishop. On August 24, 2019, Sartain issued a decree to demolish Holy Rosary Church in Tacoma, Washington, a building that has been on the City of Tacoma's Register of Tacoma Places since 1975. It had become too dangerous to occupy, and estimates for its repair were at $18 million. Pope Francis accepted his resignation as Archbishop of Seattle on September 3, 2019. The Archdiocese of Seattle, relaying a message from US nuncio Christophe Pierre, said that Coadjutor Archbishop Paul D. Eitenne automatically succeeded Sartain as Archbishop after his resignation was accepted. Sartain is also reported to be in poor health, which resulted in Pope Francis accepting his resignation.