Ephron died in a New York City hospital at about 8 p.m. ET Tuesday after a long battle with leukemia and taxing chemotherapy treatment, friends told ABC News.
The three-time Oscar-nominated filmmaker and author was one of the first women to write and direct her own films.
She is best known for writing books like "Heartburn" and "Crazy Salad" and for the movies "When Harry Met Sally," "Sleepless in Seattle" and most recently "Julie & Julia."
"Heartburn" was based on her tumultuous relationship with her second husband, journalist Carl Berstein, who helped crack in the Watergate story in the early 1970s. The couple had two sons before they split.
In 1989, Ephron married author and filmmaker Nicholas Pileggio, her third husband, with whom she lived until her death.
Ephron contributed essays and journalism to outlets including the New York Times and the Huffington Post, for which she last wrote a story in June 2011.
Ephron was raised by screenwriters in Beverly Hills before attending Wellesley College in Massachusetts.
ABC News and The Associated Press contributed to this report.