McElhone began her career in the theatre, including starring in Richard III in Regent's Park, The Count of Monte Cristo and The Cherry Orchard at the Haymarket Theatre, Leicester; and in Midsummer Night's Dream at the Open Air Theatre. McElhone made her television debut in the BBC's Bergerac in 1991, and was seen in an episode of Absolutely Fabulous in 1992.

McElhone made her film debut in 1996's Surviving Picasso with Anthony Hopkins. In the same year she was seen in the Dennis Potter TV mini-series Karaoke. Although she has made relatively few films, her most successful to date has been 1998's The Truman Show with Jim Carrey. She had leading roles opposite Robert DeNiro in Ronin and George Clooney in Solaris.

In 2005, the actress co-starred in the NBC miniseries Revelations with actor Bill Pullman. She starred in a 2006 West End production of Honour at the Wyndham's Theatre alongside Diana Rigg and Martin Jarvis. She then accepted a leading role in the sexually provocative Showtime cable television series Californication as Karen, alongside David Duchovny. McElhone is the newest Neutrogena spokeswoman and the face of the Ageless Essentials Continuous Hydration line.

• Heaven and Earth (2009) (pre-production) .... James Miranda Barry
  ... aka Barry (International: English title: informal title) (UK: working title)
  
• "Californication" .... Karen (24 episodes, 2007-2008)
       - La Petite Mort (2008) TV episode .... Karen
       - Blues from Laurel Canyon (2008) TV episode .... Karen
       - In Utero (2008) TV episode .... Karen
       - La Ronde (2008) TV episode .... Karen
       - Going Down and Out in Beverly Hills (2008) TV episode .... Karen
        (19 more)
• The Secret of Moonacre (2008) .... Loveday
  ... aka The Little White Horse (UK: copyright title)
• "The Company" (2007) TV mini-series .... Elizabet (unknown episodes)
• Big Nothing (2006) .... Penelope Wood
• Guy X (2005) .... Irene
• "Revelations" .... Sister Josepha Montafiore (6 episodes, 2005)
       - Hour Six (2005) TV episode .... Sister Josepha Montafiore
       - Hour Five (2005) TV episode .... Sister Josepha Montafiore
       - Hour Four (2005) TV episode .... Sister Josepha Montafiore
       - Hour Three (2005) TV episode .... Sister Josepha Montafiore
       - Hour Two (2005) TV episode .... Sister Josepha Montafiore
        (1 more)
• Ladies in Lavender. (2004) .... Olga Daniloff
• The Other Boleyn Girl (2003) (TV) .... Mary Boleyn
• Solaris (2002) .... Rheya
• City of Ghosts (2002) .... Sophie
• FeardotCom (2002) .... Terry Huston, Dept. of Health
  ... aka Fear Dot Com (Germany) (USA: promotional title)
• Laurel Canyon (2002) .... Sara
• Killing Me Softly (2002) .... Deborah
• Contaminated Man (2000) .... Holly Anderson
  ... aka Bei Berührung Tod (Germany)
  ... aka Contagion (UK)
• Love's Labour's Lost (2000) .... Rosaline
  ... aka Peines d'amour perdues (Canada: French title) (France)