Talmadge married Buster Keaton on May 31, 1921, after an unusual courtship where they did not see each other for two years and exchanged no love letters. 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. The reasons for marriage on both sides have never been fully explained. They had dated, but not too seriously. It was believed 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.
Their marriage resulted in two sons, James, born 1922, and Robert, born 1924, but was rocky and tumultuous. Natalie spent prodigious amounts on clothes and ever-more elaborate Beverly Hills homes, and after the birth of their second son she ceased sexual relations with Buster. Although accepting of this exile (although it was imposed on him for reasons he did not understand), Keaton made it clear to Natalie and her mother that he would not go without sex and would find other partners. At this time he was only 28.
During the next few years 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 an alcohol problem. Her hatred and enmity towards her former husband persisted for the rest of her life and she refused to speak of him.
Natalie Talmadge died of a cardiac arrest in 1969. She was buried in the family crypt in the Shrine of Eternal Love in the Abbey of the Psalms at Hollywood Forever Cemetery in Los Angeles, California.
Smith, Imogen Sara (2008). Buster Keaton: The Persistence of Comedy. Gambit Publishing. ISBN 978-0967591742.
Marion Meade (1995), Buster Keaton: Cut to the Chase, (ISBN 0-306-80802-1).