Although often recognized for her girl next door image, Shue starred as a prostitute in the 1995 film Leaving Las Vegas with Nicolas Cage. The role earned an Academy Award nomination for Best Actress. She was also nominated for a BAFTA, Golden Globe and SAG Award for Best Actress, and won the Best Actress awards at the Independent Spirit Awards, Los Angeles Film Critics Association Awards and the National Society of Film Critics Awards.

Since then, she has starred in The Trigger Effect, The Saint, Woody Allen's Deconstructing Harry, Palmetto, and Hollow Man. In 1999, Shue starred in Molly as an autistic young woman, who underwent an operation that allowed her to become more "normal." She had strong supporting roles in Hide and Seek opposite Robert De Niro and Mysterious Skin. Shue reportedly was set to co-star with Jim Carrey in The Number 23 but became pregnant just weeks before filming and ended up losing the part to Virginia Madsen. In 2007, Shue and her two brothers produced Gracie. She had a role in the film, which is set in 1978 and loosely based upon Elisabeth's own experiences as the only girl on a boys soccer team. In 2008, Shue starred in Hamlet 2 as a fictionalized version of herself; in the film, she has quit acting to become a nurse and is the favorite actress of Dana Marschz (played by Steve Coogan).

Known among her friends and family as, "Lisa," Shue is married to Davis Guggenheim, director of the HBO TV series Deadwood, An Inconvenient Truth and Gracie. Their son, Miles William, was born on November 11, 1997. She gave birth to her first daughter, Stella Street, on March 19, 2001. Her third child, Agnes Charles, was born on June 18, 2006. Her son's middle name was in honor of her second brother William, who died in 1988 at the age of 26 from a swimming accident while on family vacation.

• The Hard Ride (2009) (pre-production) (rumored) .... Agnes Lake
• Waking Madison (2009) (post-production) .... Dr. Elizabeth Barnes
• Don McKay (2009) (post-production) .... Sonny
  
• Hamlet 2 (2008) .... Elisabeth Shue
• First Born (2007) .... Laura
• Gracie (2007) .... Lindsay Bowen
• Dreamer: Inspired by a True Story (2005) .... Lily
  ... aka Dreamer (Australia: TV title)
• Hide and Seek (2005) .... Elizabeth
• Mysterious Skin (2004) .... Mrs. McCormick
• Leo (2002) .... Mary Bloom
• Tuck Everlasting (2002) (voice) .... Narrator
• Amy & Isabelle (2001) (TV) .... Isabelle Goodrow
  ... aka Oprah Winfrey Presents: Amy and Isabelle (USA: complete title)
• Hollow Man (2000) .... Linda McKay
  ... aka Hollow Man - Unsichtbare Gefahr (Germany)
  
  
• Molly (1999) .... Molly McKay
• Cousin Bette (1998) .... Jenny Cadine
• City of Angels (1998) (uncredited) .... Pregnant Woman
  ... aka Stadt der Engel (Germany)
• Palmetto (1998) .... Mrs. Donnelly / Rhea Malroux
  ... aka Dumme sterben nicht aus
• Deconstructing Harry (1997) .... Fay
• The Saint (1997) .... Dr. Emma Russell
• The Trigger Effect (1996) .... Annie Kay
• Leaving Las Vegas (1995) .... Sera
  ... aka Leaving Las Vegas (France)
• Underneath (1995) .... Susan Crenshaw
  ... aka The Underneath (USA: promotional title)
• Radio Inside (1994) .... Natalie
• Blind Justice (1994) (TV) .... Caroline
  ... aka Canaan's Way