Talmadge was born in Brooklyn, New York to Margaret L. “Peg” and Frederick O. Talmadge. She was the younger sister of Norma Talmadge and the older sister of Constance Talmadge, both of whom became film actresses.  She appeared in D.W. Griffith’s Intolerance (1916), The Passion Flower (1921) with her sister Norma, and Buster Keaton’s Our Hospitality (1923), her final film appearance.  Talmadge married Buster Keaton on May 31, 1921. She proposed to him in a letter in January of that year by saying, “I am alone now with Mother. If you still care for me just send for me.” Keaton went east from Hollywood by train and married her. It’s possible that Joe Schenck, Keaton’s producer and Norma’s husband and producer, influenced the match, possibly arguing that it would solve several problems at once and keep the business all in the family, although Keaton and Talmadge had dated in the past.

Talmadge was Roman Catholic, but the marriage was performed as a civil ceremony. Their marriage resulted in two sons, James (June 2, 1922 – February 14, 2007), and Robert (February 3, 1924 – July 19, 2009). Talmadge spent prodigious amounts on clothes and the Keatons lived in ever more elaborate Beverly Hills homes. After the birth of their second son Talmadge decided not to have any more children, resulting in the couple staying in separate rooms. Keaton was accepting of this, and the Talmadges agreed that he should keep any affairs discreet. Late in the marriage, Keaton’s career began to suffer after his contract with Schenck was sold to Metro-Goldwyn-Mayer, and in the early ’30s he began to struggle with alcoholism and become more open about his affairs with other women. Following the much-publicized divorce in 1932, Talmadge legally changed their boys’ names to Talmadge and denied them any contact with their father. The name change was especially awkward for James, who was ten years old and already accustomed to his last name.

She became involved with an actor named Larry Kent. They lived together for a while in a house bought for her by her sister Constance after the famous Italian villa mansion which Keaton had built for her had been sold in 1933. They also took vacations together on occasion, but the romance did not last.  She never remarried, and in her solitary existence also developed a drinking problem (consuming up to a quart of whiskey every day) in addition to chain smoking. Talmadge carried a vengeful hatred of her husband for the rest of her life and would not allow him to be mentioned in her presence. This eventually became a running joke in the family to the point where her grandchildren would often amuse themselves by saying Keaton’s name just to enrage her.  Natalie Talmadge was in frail health during her final years and was a resident of the Santa Monica Convalescent Home. She died of heart failure on June 19, 1969 at Santa Monica Hospital. She is buried in the Abbey of the Psalms in the Talmadge Room at Hollywood Forever Cemetery.