A native of New Rochelle, New York, Spoto graduated from Iona Preparatory School in 1959 and received his B.A. summa cum laude from Iona College in 1963 and his M.A. and Ph.D. in Theology (New Testament studies) from Fordham University in 1966 and 1970, respectively. He taught at Fairfield University, at the College of New Rochelle and at the New School for Social Research from 1966 until 1986 and then at University of Southern California, beginning in 1987. He was also a visiting lecturer at the British Film Institute and the National Film Theatre in London from 1980 until 1986.

In the middle-to-late 1970s, he began writing biographies of film directors and other film and stage celebrities. More recently, he has alternated between the celebrity biographies and accounts of such religious figures as Jesus and St. Francis of Assisi. The latter was made into a television program of the same title, Reluctant Saint: Francis of Assisi, "produced for Faith & Values Media by Lightworks Producing Group and West Egg Studios." Spoto's Jacqueline Bouvier Kennedy Onassis: A Life was adapted into a four-hour drama which aired in 2000 on the U.S. Broadcast Network CBS. The production featured Joanne Whalley, Tim Matheson, Tom Skerritt, Francis Fisher, Andrew McCarthy, Phillip Baker Hall, Fred Ward and Diane Baker. Spoto was an executive producer of the project, along with George Stelzner of West Egg Studios.

Spoto serves (or has served) on the boards of directors of Human Rights Watch, Death Penalty Focus and the San Francisco-based Youth Law Center.

Spoto lives with his husband, Danish artist and school administrator Ole Flemming Larsen, near Copenhagen in Denmark.

Barry Forshaw, in the [The Times], describes Spoto as "one of the most perspicacious biographers, a man whose insights into his subjects are always razor-sharp." Michael Coveney, in the Guardian, describes Spoto as "an American quasi-academic gossipmonger who has produced zestful, authoritative books..." , and Publishers Weekly calls his life of Laurence Olivier "a magnificent, moving biography worthy of its protean subject."

Spoto has published 26 books:

• The Art of Alfred Hitchcock" (1976; rev. ed. 1999), Doubleday Anchor
• Stanley Kramer, Film Maker (1978), Putnam
• Camerado Hollywood (1978), Plume
• The Dark Side of Genius: The Life of Alfred Hitchcock (Mohsen Amiri translates it into Persian) (1983), Little, Brown & Co.
• The Kindness of Strangers: The Life of Tennessee Williams (1985), Little, Brown & Co.
• Falling in Love Again: Marlene Dietrich (1985), Little, Brown & Co.
• Lenya: A Life (1989), Little, Brown & Co.
• Madcap: The Life of Preston Sturges (1990) Little, Brown & Co.
• The Art of Alfred Hitchcock: Fifty Years of His Motion Pictures (1976), Brodart Co.; 2nd ed. (1991), Anchor
• Laurence Olivier: A Biography (1992) HarperCollins
• Blue Angel: The Life of Marlene Dietrich (1992), Doubleday
• Marilyn Monroe: The Biography (1993), Harper Collins
• A Passion for Life: The Biography of Elizabeth Taylor (1995) HarperCollins
• The Decline and Fall of the House of Windsor (also published as: Dynasty: The Turbulent Saga of the Royal Family from Victoria to Diana) (1995) Simon and Schuster
• Rebel: The Life and Legend of James Dean (1996), HarperCollins
• Diana: The Last Year (1997), Random House
• Notorious: The Life of Ingrid Bergman (1997), HarperCollins
• The Hidden Jesus: A New Life (1998), St. Martin's Press
• Jacqueline Bouvier Kennedy Onassis: A Life (2000), St. Martin's Press
• Reluctant Saint: The Life of Francis of Assisi (2002), Viking Press
• In Silence: Why We Pray (2004), Viking Press
• Enchantment: The Life of Audrey Hepburn (2006), Harmony
• Joan: The Mysterious Life of the Heretic Who Became a Saint (2007), HarperSanFrancisco
• Otherwise Engaged: The Life of Alan Bates (2007) Hutchinson
• Spellbound by Beauty: Alfred Hitchcock and His Leading Ladies (2008) Hutchinson
• High Society: The Life of Grace Kelly (2009), Harmony
• "Possessed: The Life of Joan Crawford" (2010), Morrow