Murphy landed her first job in Hollywood when she was age 14, starring as Brenda Drexell in the series Drexell's Class. She then went on to play Molly Morgan in the short-lived The Torkelsons spinoff Almost Home. Murphy also guest-starred on several television series, including Parker Lewis Can't Lose, Blossom and Frasier. She also had recurring roles on Sister, Sister; Party of Five and Boy Meets World.
Murphy starred in several films, including Clueless (1995); Girl, Interrupted (1999); Drop Dead Gorgeous (1999); Don't Say a Word (2001); the TV adaption of the novel The Devil's Arithmetic (2001); 8 Mile (2002) and Uptown Girls (2003) as well as many lesser-known films, such as Spun (2002). In 2004, she starred in the romantic comedy Little Black Book, and the critically acclaimed Sin City (2005). She starred in two Edward Burns films: Sidewalks of New York (2001) and The Groomsmen (2006). Film critic Roger Ebert acclaimed her acting talent, giving good reviews to several of her films and comparing her to Lucille Ball. In 2009, she was cast in the Lifetime TV movie, Tribute, as the main character, Cilla. She was set to appear in the Sylvester Stallone film, The Expendables, which will be released in 2010.
She was nominated for an Annie Award for voice acting in the King of the Hill episode "Movin' On Up."
Murphy completed her last film, the thriller/drama Abandoned, in June 2009. The film is scheduled for release in 2010.
In November 2009, Murphy left the production of the The Caller, which was being filmed in Puerto Rico, and was replaced by Rachelle Lefevre. Murphy denied media reports that she had been fired from the project after being difficult on set, and cited "creative differences".