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Shatner has been married four times: to Gloria Rand from 1956 to 1969, Marcy Lafferty  from 1973 to 1994, Nerine Kidd from 1997 to 1999, and his current wife Elizabeth Martin whom he married in 2001. Shatner has three daughters, Leslie Carol (b. 1958), Lisabeth Mary (b. 1960), and Melanie (b. 1964), from his marriage to Rand. Melanie had a brief career as an actress and is now the proprietor of Dari, an upscale women's clothing boutique. In his spare time, Shatner enjoys breeding and showing American Saddlebreds and Quarter Horses. Shatner has a 360-acre (1.5 km²) horse farm in Kentucky named Bellreve, where he raises the winning horses.

He is Joel Gretsch's father-in-law; Gretsch is married to Shatner's daughter, Melanie Shatner and father of his two granddaughters, Kaya and Willow.

On August 9, 1999, Shatner returned home around 10 p.m. to discover the body of his wife Nerine at the bottom of their back yard swimming pool. Alcohol and Valium were detected in an autopsy, and a coroner ruled the death an accidental drowning. The LAPD ruled out foul play and the case has been long closed. Speaking to the press shortly after his wife's death, a clearly shaken and emotional Shatner said that she "meant everything" to him and called her his "beautiful soulmate." Shatner urged the public to support Friendly House, a non-profit organization that helps women re-establish themselves in the community after suffering from alcoholism and drug addiction. He later told Larry King in an interview that "...my wife, whom I loved dearly and who loved me, was suffering with a disease that we don’t like to talk about, alcoholism. And she met a tragic ending because of it."

In 2000 a Reuters story reported that Shatner was planning to write and direct The Shiva Club, a dark comedy about the grieving process inspired by his wife's death. The project is still in pre-production. Shatner's 2004 album Has Been produced with Ben Folds included a spoken word piece titled "What Have You Done" which describes his anguish upon discovering his wife's body in the pool.