In the 1980s, Ryan appeared in Top Gun (1986), Promised Land (1987), and the Rob Reiner-directed romantic comedy When Harry Met Sally... (1989), for which she earned a Golden Globe nomination.

They had previously been the romantic leads, with Ryan playing three different women, in John Patrick Shanley's Joe Versus the Volcano in 1990 — a commercial disappointment which later developed a cult following.

She was offered the role of FBI agent Clarice Starling, the protagonist of The Silence of the Lambs (1991), but rejected it due to the film's gruesome and violent themes.

In 1994, Ryan played an alcoholic high-school guidance counselor – far from the romantic-comedy ingenue roles for which she had become famous – in Luis Mandoki's social romantic drama When a Man Loves a Woman, also starring Andy Garcia.

[13] A critic for Variety called the film "a first-class production, accentuated by fine performances and an unflinching script,"[14] and another praised Ryan for her "roller-coaster role".

The film centers on a mechanic and a Princeton doctoral candidate who fall in love, with the aid of the graduate student's uncle, Albert Einstein (played by Walter Matthau).

City of Angels (an American remake of Wim Wenders' Wings of Desire) drew positive reviews and earned nearly $200 million worldwide.

You've Got Mail, reteaming Ryan with Hanks, earned her a third nomination for the Golden Globe Award for Best Actress – Motion Picture Comedy or Musical and made more than $250 million worldwide.

Ryan's first film of the 2000s was Hanging Up, a Diane Keaton-directed family comedy-drama about a trio of sisters who bond over the approaching death of their curmudgeonly father.

Also starring Keaton, Lisa Kudrow and Walter Matthau, the film adaptation of Delia Ephron's 1995 novel received poor reviews from critics.

In the film, she portrayed the distraught wife of a kidnapped engineer, played by David Morse, while relying on a resourceful troubleshooter who makes a profession of dealing with international bandits.

While the film became a lukewarm critical and commercial success, grossing $63 million worldwide, it garnered much reportage in the tabloid press in association with Ryan and Crowe's affair.

[21] In 2003, Ryan broke away from her usual roles, starring alongside Mark Ruffalo and Jennifer Jason Leigh in Jane Campion's erotic thriller film In the Cut.

Co-producer Nicole Kidman had originally been cast in the lead, but the actress eventually dropped out after five years of development, leaving the role to Ryan, who appeared nude in a lengthy and rather graphic love scene for the first time in her career.

[25][26] Three years after the interview aired, Ryan explained that she felt Parkinson was berating her for performing nudity and had attempted to disagree with his views respectfully.

Garnering generally mixed to negative reviews, it failed to draw interest among film studios, resulting in a straight-to-DVD release in January 2009.

[34] In his review for Variety, Peter Debruge said, "The characters seem to be doing all the laughing, while the general public has nothing to cling to but the horndog flirtation between mismatched leads William H. Macy and Meg Ryan—hardly ideal ingredients for mainstream success.

[36] Co-starring Colin Hanks, Selma Blair and Antonio Banderas, the action comedy received overwhelmingly negative reviews, with David Nusair of Reel Film noting it "an unmitigated disaster virtually from its opening frames".

[37] Written, produced and directed by Diane English, the film centers on a group of four female Manhattan socialites whose primary interest is idle gossip, with Ryan portraying a wealthy woman whose husband is cheating on her with a shop girl, played by Eva Mendes.

In this film, directed by actress Cheryl Hines and based on a screenplay by late writer Adrienne Shelly, who was murdered a year prior to filming, Ryan portrayed a high-powered female attorney who learns that her husband, played by Timothy Hutton, is about to leave their troubled marriage, and decides to hold him captive by duct-taping him to a toilet.

In April 2011, it was announced that Ryan would make her feature film directing debut in Into the Beautiful, described as "a contemporary Big Chill with longtime friends reconnecting", but it was never made.

In October 2013, it was reported that Ryan would be returning to television to produce and star in a new comedy for NBC revolving around a former hotshot New York editor, for which it again failed to get production approval.

[63] Journalist Jane Pauley, as well as Kate Erbland of IndieWire, recognized Ryan as one of the leading ladies responsible for the genre's resurgence,[64][65] earning her the nickname the "Queen of Rom-coms".

[66][67][68] Benjamin Lee of The Guardian attributes Ryan's association with the genre to her "endless source of warmth and charisma, boasting a magic, ineffable charm that only a handful of other actors have ever truly had".

[59] For much of her career, Ryan typically played cheerful, witty,[70] and quirky women in romantic comedies,[71] but she has also starred in thrillers, dramas, and action films.

[73][74] Described as an embodiment of the girl next door archetype,[2][73] the media dubbed Ryan "America's sweetheart" due to both her wholesome on and offscreen personas,[68] a label she admitted to feeling conflicted about.

[26] Ryan's public image also suffered from rumors that she had cheated on then-husband Dennis Quaid with Proof of Life (2000) co-star Russell Crowe.

[58] Ryan is particularly fond of movies from the 1930s, 1940s, and 1950s, citing actors Claudette Colbert, Clark Gable, Carole Lombard, Katharine Hepburn and Jimmy Stewart as personal favorites and influences of hers.