But her new film, "Something's Gotta Give," is a new career high for this actress, who many still think of as Annie Hall. And it's a breakthrough part that has forced her to slough off her buttoned-up image – and her clothes.
This role is out of character for Keaton, who showed up at an interview with Anchor Lesley Stahl in Hollywood dressed in a pantsuit and wearing black gloves.
"You work so hard to hide yourself and cover up," says Stahl to Keaton. "And you're wearing gloves. We're in Los Angeles, honey!"
"I know, I know," says Keaton, laughing. "It's frightening, isn't it?"
In "Something's Gotta Give," Keaton plays a controlling woman who's just too busy and successful for romance. But she soon finds herself in two love affairs.
Director Nancy Meyers wrote the script knowing exactly which actors she wanted for the parts: Jack Nicholson as the commitment-phobic bachelor who dates only younger women, and Keaton as his unexpected soul mate.
"She's absolutely hilarious and unpredictable, which is part of what makes her so funny. Because you don't see some of this coming," says Meyers, who would have to convince the studio that a story about an older woman finding love would sell -- and that a 50-something woman should play the part.
"Let's go with the girl that's the most right for the part," adds Meyers. "The one that I wrote it for and the one I knew could, you know, knock it out of the ballpark."
"I remember sitting at the restaurant, thinking good luck. Good luck getting me. Good luck because it's not gonna be easy, because you need everybody to sign off. You need Jack, you need the studio," says Keaton. "I've been saved so many times … It's simply money. I haven't been like Jack, the legendary monumental moneymaker the likes of which we'll never see again."
Sony pictures bought the idea, but Meyers still had to get Keaton to sign off on one last thing – taking her clothes off. "Diane is a beautiful looking woman of her age," says Meyers. "Of course, the big secret, which none of us knew, was she had this amazing body, you know. So only Diane knew this…"
"The reason that I am in such great shape is because the shot was about one second long. Do you understand what I mean," says Keaton. "They saw nothing. It was nice and far away. And I had on body makeup. And Ahhh! That's all I did!"
Actually, it was two seconds long, and a daring move for a 58-year-old actress who is clearly not set in her ways.
When Keaton first started out on Broadway, she refused to take off her clothes -- a tough stance considering she was in "Hair" and everyone in the cast got naked.
"Change. Let's get back to change. Life changes. And also I believe I have a very different attitude about my body," says Keaton, laughing. "What I'm happy about with my body these days is that it works, that it functions, that I can walk."
It's that self-deprecation that is true Keaton -- and has been for more than 40 films -- many of them classics.
"We were all riveted to her in 'Annie Hall,' which is the movie we all really sort of first noticed her in. She's like a brand new kind of movie star and movie heroine," says Meyer.
She won an Academy Award for that performance. In the "Godfather" saga, she went from Al Pacino's innocent girlfriend to his embittered wife. In "Reds," she played a passionate writer in love with Warren Beatty. And in the "First Wives Club," she took the role of a jilted ex-wife and made it funny.
But Keaton says she doesn't consider herself a great movie star: "I think I'm a good collaborator. I think I'm a good team player, and I think that sometimes I get these roles where I have this opportunity. And they're almost invariably romantic comedy."
This latest film is her fourth with Meyers, who wrote and produced "Baby Boom" and "Father of the Bride." One of the most important moments in this new movie is the love scene between middle-aged Keaton and middle-aged Nicholson.
"Nancy kept saying it's going to be open. We're going to be open," recalls Keaton. "I kept saying to her, 'Well, can't I wear my glasses,' and, 'You said turtlenecks. I mean, can't I keep the turtlenecks on?'"
But she says working with Nicholson was easy: "You just grab his face. He just lets you do anything to him. It's just so much fun. Come on, that's what you want in life when you're acting. You don't want somebody worried about this, worried about that, you just wanna. He just lets you do anything to him, he doesn't care what you do to him. And that is just heaven to act with."
In the film, Keaton is not only pursued by Nicholson, but also by an obviously much-younger man -- Keanu Reeves.
"It's a great fantasy to play. I, you know, not for me," says Keaton. "Not for me. No. Uh uh."
So, what's the actress who's been linked with so many famous men, looking for in terms of romance these days?
It turns out, nothing.
"I think that you know my feeling about romantic love is that people worship you and kiss you and tell you you're beautiful and all these ridiculous things that just really, I mean, they're sweet in a moment," says Keaton.
"Obviously, I meant they're transporting, but the thing is, you get addicted to that. And that's not real love to me. This idea of romantic love is a very dangerous area for a person like me."
Her love life right now, she says, is all about her two children. Keaton adopted a boy and a girl, and became a single mother in her 50s.
"To raise a child is the most humbling experience in life," says Keaton. "And I think that is glorious in and of itself - the fact that you really are put right back on the planet earth, firmly with your two feet. You know where you are, you are raising children and they are astonishing."
However she feels about love and marriage, Keaton's performance as the woman who discovers it's never too late to open your heart, has touched a chord, especially with older women.
"The way Diane Keaton plays this part elevates 'Something's Gotta Give' from the slick Hollywood comedy that it otherwise would be, to something a little bit more resonant and emotionally honest," says Mark Harris, editor-at-large at Entertainment Weekly magazine.
"You see her exhilarated at having suddently started an affair. Frightened about what she's feeling. And angry with herself for letting herself become this vulnerable. You see the play of all those feelings in her performance."
Keaton has already been recognized with a Golden Globe for her performance in "Something's Gotta Give," and critics believe she has a shot at walking from the red carpet right onto the state at the Academy Awards.
Does she want it?
"I think that, Oh, I don't know what to say. It would be great. Of course it would be great," says Keaton.
"But you don't sit around worrying about it," asks Stahl.
"No," says Keaton. "How could I worry about it right now, when this has been such an amazing year for me just as it is."