The three-time Oscar nominee "passed away June 26, 2012 at 7:40 pm at New York Presbyterian/Weill Cornell Medical Center surrounded by her family. The cause of death was acute myeloid leukemia," her family tells PEOPLE in a statement.
"We thank you all for your thoughts."
A writer and director who was as comfortable with romantic comedies as she was with hard-hitting dramas with social themes, Ephron's films featured strong female roles that attracted such A-listers as Meg Ryan, Meryl Streep, Amy Adams and Cher.
The daughter of playwrights and sister to three other writers, Nora was married and divorced to author Dan Greenberg before marrying Watergate investigative reporter Carl Bernstein. She based her searing novel and screenplay Heartburn on the collapse of their marriage.
She also wrote the screenplays for the drama Silkwood (starring Streep and Cher) about nuclear activist Karen Silkwood, but was best known – and reached the highest levels of success – with her lighter fare.
Described both affectionately – and sometimes not – as "chick flicks," the wildly successful trio of Harry, Sleepless and Mail (co-written with sister Delia), had Ryan falling in love with Billy Crystal or Tom Hanks – and turned the actress into a mega-star.
Ephron's last film was the time-shifting Julia Child foodie flick Julie & Julia and in 2008 she wrote a bestseller about aging called I Feel Bad About My Neck.
At the time of her death she was married to her third husband, Goodfellas writer Nicholas Pileggi.
Per the family, donations may be made in her honor to The Public Theater and The Motion Picture and Television Fund.