Ephron died of complications from myelodysplasia, a blood disorder she was diagnosed with six years ago, The Washington Post reports.
The beloved screenwriter, who brought to life award-winning films including "Silkwood," "When Harry Met Sally...," "Sleepless in Seattle," "You've Got Mail" and, most recently "Julie & Julia," belonged to America's top tier of filmmakers, but her talents extended far beyond Hollywood. Ephron was also an accomplished essayist, novelist and reporter, not to mention the Editor-at-Large of The Huffington Post.
Raised in Beverly Hills, Ephron graduated from Wellesley College before beginning her career as a journalist at the New York Post. She then went on to write about the 1970s women's movement for Esquire.
"Whatever you choose, however many roads you travel, I hope that you choose not to be a lady," Ephron told Wellesley's Class of 1996 in a commencement speech. "I hope you will find some way to break the rules and make a little trouble out there. And I also hope that you will choose to make some of that trouble on behalf of women."
Ephron had the wit and the guts to follow her own advice.
"She was the funniest feminist, or pseudofeminist, depending on whom you ask," Ariel Levy observed in a 2009 profile of Ephron published by The New Yorker.
In her work and in her life, Ephron refused to settle for predictability. "Every 10 years or so there was a moment when I'd say, even subconsciously, 'Is that all there is?'" she told Ladies' Home Journal in 2009. "You've got to find ways to keep it fresh for yourself. To do the thing, as they say, that is a stretch."
In 1976, Ephron married Washington Post journalist Carl Bernstein (she was previously married to writer Dan Greenburg for nine years) on the heels of his induction into the journalism hall of fame. Bernstein and his fellow reporter Bob Woodward had chased down the Watergate scandal, which ended the presidency of President Richard Nixon.
"Carl and Nora were the Brad and Jen of the early eighties," Levy wrote.
Like many power couples, this one ended in divorce -- after four years.
Following her second divorce, Ephron wrote the Academy Award-winning screenplay for "Silkwood," starring Kurt Russell and Meryl Streep. Ephron and Streep would collaborate again on 1986's "Heartburn" and 2009's "Julie & Julia."
"Directing movies is the best job there is, that's all," Ephron told the UK's Independent in 1993. "I can hardly say a word after that. It's just a great job. I just want to go on making movies, and some of them will be completely meaningless, except, of course, to me."
Ephron is perhaps best known for her 1989 film, "When Harry Met Sally...," which has become a cultural mainstay.
"'When Harry Met Sally...' is kind of a dark movie," director Nicolas Stoller told The Huffington Post in 2012. "It's sweet and it ends beautifully and romantic, but those are two pretty messed up characters. They're pretty flawed. They do pretty nasty things to each other. It goes to a dark, pretty real place between them. That's why it's a classic. [Screenwriter] Nora Ephron does not pull her punches in that movie."
Tom Hanks, who starred in not one, but two now-classic Ephron rom-coms -- "Sleepless in Seattle" (1993) and "You've Got Mail" (1998) -- said, "Working on a movie with Nora is kind of like going to a dinner party of hers," Hanks said of Ephron. "There's a lot of great conversation. There's a certain amount of screwing around but, by and large, you wind up talking about what Nora dictates you're going to wind up talking about."
In recent years, Ephron had grown increasingly aware of her mortality. In her latest book, "I Remember Nothing: And other Reflections" (2010) she writes: "You do get to a certain point in life where you have to realistically, I think, understand that the days are getting shorter, and you can't put things off thinking you'll get to them someday. If you really want to do them, you better do them. There are simply too many people getting sick, and sooner or later you will. So I'm very much a believer in knowing what it is that you love doing so you can do a great deal of it."
Ephron is survived by her husband, screenwriter Nicholas Pileggi and her two sons, Jacob and Max Bernstein. A memorial has been planned for Thursday, June 28, in New York.