Her first full-blown hit in a leading role was the romantic comedy When Harry Met Sally... (1989) which paired her with comedic leading man Billy Crystal. Her portrayal of Sally Albright, which earned her a Golden Globe nomination, is memorable for her depiction of a theatrical faked orgasm in Katz's Delicatessen in Manhattan. The film would be the first of three successful Nora Ephron films in which Ryan would be cast as a bubbly, feisty, incurable romantic. Ryan then starred in The Doors and in Prelude to a Kiss. Both films were moderately successful. 1993 saw the release of the hugely successful romantic comedy Sleepless in Seattle, which paired Ryan with leading man Tom Hanks for the second of three times. (The first was in Joe Versus the Volcano, which earned a "cult following" but was a critical and commercial disappointment.)

She made several attempts to break away from the romantic comedy ingenue stereotype and garnered critical acclaim for her work in When a Man Loves a Woman, in which she played an alcoholic and in Courage Under Fire, portraying a captain in the Gulf War. Both films were substantial successes at the box office. Many of her films of the 1990s were hits not only in North America, but also abroad. In 1994, Ryan won Harvard's Hasty Pudding Woman of the Year. That same year, People Magazine dubbed her one of "the 50 most beautiful people in the world." In 1995, critic Richard Corliss called her the, "the current soul of romantic comedy." That same year, she appeared opposite Kevin Kline in Lawrence Kasdan's, French Kiss, a romantic comedy that catered to her America's Sweetheart persona. The film was a huge success worldwide, grossing slightly over $101 million.

In 1997, Ryan voiced the lead role in the animated film, Anastasia, which garnered good reviews and enjoyed box office success. In 1998, Ryan starred in two films. The first, City of Angels, drew negative reviews, but became a huge financial success, topping nearly $200 million worldwide. You've Got Mail, which once again paired Ryan with Tom Hanks, earned her a third Golden Globe nomination and made over $250 million worldwide. In 2000, Ryan starred in the action thriller Proof of Life, opposite Russell Crowe. Though the film was a critical and commercial flop, her $15 million paycheck established her as one of the highest paid actresses in Hollywood.

That same year, Ryan starred opposite Diane Keaton in the comedy, Hanging Up, which received poor reviews, but grossed over $51 million. A year later, she once again returned to her romantic comedy roots in the film, Kate & Leopold. The film was well-received by some critics, but failed to find an audience. In 2003, she broke away from her usual roles, starring in Jane Campion's erotic crime thriller In the Cut. Though Ryan's decision to appear nude in a lengthy and rather graphic love scene for the first time in her career earned her much media attention, the movie failed with critics and grossed only $23 million in theaters. In October 2003, while in the UK to promote, "In the Cut," Ryan's controversial interview with Michael Parkinson on the long-running television talk show Parkinson brought her some negative publicity in the British press.

• Serious Moonlight (2009) (post-production) .... Louise
  
• The Women (2008/I) .... Mary Haines
• My Mom's New Boyfriend (2008) .... Martha (Marty) Durand
  ... aka Lauschangriff - My Mom's New Boyfriend (Germany: DVD title)
  ... aka My Spy (Australia: DVD title)
• The Deal (2008/I) .... Deidre Hearn
  ... aka Start Shooting (Europe)
• "The Simpsons" .... Dr. Swanson (1 episode, 2007)
       - Yokel Chords (2007) TV episode (voice) .... Dr. Swanson
• In the Land of Women (2007) .... Sarah Hardwicke
• Against the Ropes (2004) .... Jackie Kallen
  ... aka Die Promoterin (Germany)
  ... aka The Promoter (Germany)
• In the Cut (2003) .... Frannie
• Kate & Leopold (2001) .... Kate McKay
• Proof of Life (2000) .... Alice Bowman
• Hanging Up (2000) .... Eve Mozell Marks
  ... aka Aufgelegt! (Germany)
  
• You've Got Mail (1998) .... Kathleen Kelly
• Hurlyburly (1998) .... Bonnie
• City of Angels (1998) .... Dr. Maggie Rice
  ... aka Stadt der Engel (Germany)
• Anastasia (1997) (voice) .... Anastasia
• Addicted to Love (1997) .... Maggie
  ... aka Forlorn
• Courage Under Fire (1996) .... Karen Walden
• Restoration (1995) .... Katharine
• French Kiss (1995) .... Kate