In 1990, she won acclaim for her portrayal of Jim Morrison’s drugged-out mistress in Oliver Stone’s The Doors (1991), starring Val Kilmer; she also turned in an emotionally-charged performance as a woman struggling with alcoholism in When a Man Loves a Woman (1994), co-starring Andy Garcia. Other more serious films for Ryan included the period comedy Restoration (1995); Courage Under Fire (1996), a military drama co-starring Denzel Washington; the black comedy Addicted to Love (1997), co-starring Matthew Broderick; City of Angels (1998), with Nicolas Cage; and the little-seen ensemble drama Hurlyburly, starring Sean Penn and Kevin Spacey. She also lent her famous voice to the title character in the 1997 animated feature Anastasia, about the lost daughter of the murdered Russian royal family.

In 2000, Ryan returned to the lightweight romantic comedy genre with Hanging Up, a film written by Ephron’s sister Delia, directed by Diane Keaton, and co-starring Keaton, Lisa Kudrow, and Matthau. In the romance/adventure Proof of Life, released in December of 2000, she starred as the wife of an American kidnapped by South American terrorists, who turns to a hostage negotiator, played by Russell Crowe, for help. A remake of the classic George Cukor film The Women (1939, based on the play by Clare Booth Luce) is reportedly in the works, co-starring Ryan and Julia Roberts.

While filming the critically panned comedy Innerspace (1987), Ryan fell in love with her co-star, Dennis Quaid. The couple appeared in two more films together, D.O.A. (1988) and Flesh and Bone (1993); both films met with little success. Ryan and Quaid married in 1991 (after Quaid underwent a highly publicized rehabilitation from his addiction to cocaine) and have one son, Jack Henry. The couple, who have homes in California and Montana, announced their separation in June 2000. At the same time, Ryan became romantically involved and was linked in the press to Crowe, her costar in the upcoming Proof of Life. Citing "irreconcilable differences" (and claiming there was no third party involved), Quaid filed for divorce in July 2000. Ryan and Crowe split in late December of that year. The Quaid-Ryan divorce was finalized in July 2001, but the couple remain friends and will have joint custody of their son.