The author and screenwriter had fought a six-year battle with leukemia and finally succumbed to the disease, reported CNN online.
Ephron's son Jacob Bernstein confirmed her death in Manhattan yesterday.
She earned three Oscar nominations for her screenwriting and her work was among the most quotable and influential of her generation.
She was married to screenwriter Nicholas Pileggi.
Colin Hanks, son of Tom Hanks who starred in some of her best-loved movies, said, "Nora Ephron was devastatingly funny, extremely witty, and was ALWAYS one of the kindest people I have ever met."
"You can settle for reality, or you can go off, like a fool, and dream another dream." ? Nora Ephron. Oh Jeez... You will be missed... RIP XO," posted actress Kirstie Alley on Twitter.
"An amazingly talented girl who was able to accomplish everything she set her mind to with great style and will be missed enormously," actor Martin Landau said in a statement.
Ephron also wrote and directed "Julie & Julia," which earned Meryl Streep a best actress Oscar nomination in 2010.