Banks changed her name to avoid confusion with actress Elizabeth Mitchell. She debuted in the independent film Surrender Dorothy as "Elizabeth Casey." Banks is known for her roles in Seabiscuit, Heights, the Spider-Man films (playing the part of Betty Brant), and the cult comedy Wet Hot American Summer. She quickly gained widespread exposure through movies like The 40-Year-Old Virgin and Slither. She also plays Mark Wahlberg's love interest in the movie Invincible. In May 2006, she appeared in the season five finale of the NBC comedy-drama Scrubs as Dr. Kim Briggs, the love interest of J.D. (Zach Braff). The character has appeared throughout season six and seven as a recurring guest star.

In 2005, she appeared on the show Stella. In 2007, Banks played the female lead in the comedy Meet Bill, alongside Aaron Eckhart and Jessica Alba. Banks also has a small role in the 2007 Christmas comedy film Fred Claus, co-starring Vince Vaughn and Paul Giamatti, and played a love interest in the 2008 comedy Definitely, Maybe alongside Isla Fisher and Ryan Reynolds. Banks starred with Seth Rogen as the eponymous female lead in the Kevin Smith comedy, Zack and Miri Make a Porno, which was released on Halloween 2008. She was also seen playing United States First Lady Laura Bush in Oliver Stone's biopic on the life of President George W. Bush, W.

She has appeared in the thriller The Uninvited, a remake of the Korean horror film A Tale of Two Sisters. The film tells the tale of an intrusive stepmother who makes life miserable for the teen daughters of her new husband. Banks based her character Rachel on Rebecca De Mornay in The Hand that Rocks the Cradle". It was very important to me that every line reading I gave could be interpreted two ways," says Banks of her role, "So that when you go back through the movie you can see that".

Banks is a frequent co-star of actor Paul Rudd, the two having appeared in four films together to date (Wet Hot American Summer, The Baxter, The 40 Year Old Virgin, and Role Models). She does not have any projects in production at this time. "There was a David O. Russell movie that I really wanted to make with Vince Vaughn that ended up falling apart", said Banks, referring to the film H-Man Cometh, in a January 2009 interview.

• The H-Man Cometh (2010) (pre-production)
  
• The Uninvited (2009) .... Rachael
• "American Dad!" .... Lisa Silver / ... (3 episodes, 2007-2008)
       - Escape from Pearl Bailey (2008) TV episode (voice) .... Lisa Silver
       - 1600 Candles (2008) TV episode (voice) .... Lisa Silver
       - The Vacation Goo (2007) TV episode (voice) .... Becky Arangino
• Role Models (2008) .... Beth
  ... aka Vorbilder?! (Germany)
• W. (2008/I) .... Laura Bush
  ... aka Oliver Stone's W. (Germany: TV title)
  ... aka W. - Ein missverstandenes Leben (Germany: DVD title)
• Zack and Miri Make a Porno (2008) .... Miriam Linky
  ... aka Zack and Miri (USA: bowdlerized title)
• Lovely, Still (2008) .... Alex
• "Wainy Days" .... Shelly (3 episodes, 2007-2008)
       - Shelly II (2008) TV episode .... Shelly
       - The Date (2007) TV episode .... Shelly
       - Shelly (2007) TV episode .... Shelly
• Meet Dave (2008) .... Gina Morrison
• Definitely, Maybe (2008) .... Emily
  ... aka Un jour, peut-être (France)
• "Comanche Moon" (2008) TV mini-series .... Maggie
• Fred Claus (2007) .... Charlene
• "[scrubs]" .... Dr. Kim Briggs (13 episodes, 2006-2007)
       - My Hard Labor (2007) TV episode .... Dr. Kim Briggs
       - My Own Worst Enemy (2007) TV episode .... Dr. Kim Briggs
       - My Point of No Return (2007) TV episode .... Dr. Kim Briggs
       - My Rabbit (2007) TV episode .... Dr. Kim Briggs
       - My Conventional Wisdom (2007) TV episode .... Dr. Kim Briggs
        (8 more)
• Bill (2007) .... Jess
  ... aka Meet Bill (USA: new title)
• Spider-Man 3 (2007) .... Miss Brant
  ... aka Spider-Man 3: The IMAX Experience (USA: IMAX version)
• Invincible (2006) .... Janet Cantrell
• Slither (2006) .... Starla Grant
  ... aka Incisions (Canada: French title)
• Daltry Calhoun (2005) .... May