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In June 1988, following the success of The Vampire Lestat and with The Queen of the Damned about to be published, the Rices purchased a second home in New Orleans, the Brevard–Rice House, built in 1857 for Albert Hamilton Brevard. Stan took a leave of absence from his teaching, and together they moved to New Orleans. Within months, they decided to make it their permanent home.

Rice returned to the Catholic Church in 1998 after decades of atheism. On December 14, 1998, she fell into a coma, later determined to be caused by diabetic ketoacidosis (DKA), and nearly died. She was later diagnosed with diabetes mellitus type 1, and was insulin-dependent.Burke, Anne. "An Interview with Anne Rice"  SFSU Magazine Online, Spring 2006. In 2003, following the recommendation of her husband and carried out shortly after his death, Rice underwent gastric bypass surgery and shed 103 pounds.Adato, Allison. "Chapter Two: In a Newly Trim Body, Author Anne Rice Is Starting a New Life—One Without Her Beloved Husband or Favorite Vampire"  People Magazine, Vol. 60, No. 25, December 22, 2003.

In 2004, Rice nearly died again from an intestinal blockage or bowel obstruction, a common complication of gastric bypass surgery. In 2005, Newsweek reported, "[Rice] came close to death last year, when she had surgery for an intestinal blockage, and also back in 1998, when she went into a sudden diabetic coma; that same year she returned to the Roman Catholic Church, which she'd left at 18." Her return did not come with a full embrace of the Church's stances on social issues; Rice remained a vocal supporter of equality for gay men and lesbians (including marriage rights), as well as abortion rights and birth control, writing extensively on such issues.

In October 2005, while promoting her book, Christ the Lord: Out of Egypt, she announced in Newsweek that she would now use her life and talent of writing to glorify her belief in God, but she did not renounce her earlier works, citing a connection in her earlier work with the state of her spiritual life.

In the Author's Note from Christ the Lord: Out of Egypt, Rice states:

I had experienced an old-fashioned, strict Roman Catholic childhood in the 1940s and 1950s ... we attended daily Mass and Communion in an enormous and magnificently decorated church.... Stained-glass windows, the Latin Mass, the detailed answers to complex questions on good and evil—these things were imprinted on my soul forever....

I left this church at age 18.... I wanted to know what was happening, why so many seemingly good people didn't believe in any organized religion yet cared passionately about their behavior and value of their lives.... I broke with the church.... I wrote many novels that without my being aware that they reflected my quest for meaning in a world without God.

In her memoir Called Out of Darkness: A Spiritual Confession, Rice stated:

In the moment of surrender, I let go of all the theological or social questions which had kept me from [God] for countless years. I simply let them go. There was the sense, profound and wordless, that if He knew everything I did not have to know everything, and that, in seeking to know everything, I'd been, all of my life, missing the entire point. No social paradox, no historic disaster, no hideous record of injustice or misery should keep me from Him. No question of Scriptural integrity, no torment over the fate of this or that atheist or gay friend, no worry for those condemned and ostracized by my church or any other church should stand between me and Him. The reason? It was magnificently simple: He knew how or why everything happened; He knew the disposition of every single soul. He wasn't going to let anything happen by accident! Nobody was going to go to Hell by mistake.