In 1997, after graduating from high school, Lohman moved to Los Angeles, California to pursue her acting career. For the next few years, her work consisted of science fiction B-movies (such as Kraa! The Sea Monster and Planet Patrol), television productions (including the made-for-TV movie Sharing the Secret) and children's films (such as Delivering Milo and The Million Dollar Kid). Also included was the dark urban drama White Boy. Lohman starred in White Oleander, an adaptation of Janet Fitch’s novel, alongside Michelle Pfeiffer, Robin Wright-Penn and Renée Zellweger. Though the film was unsuccessful at the box office (it opened to $5.6 million in 1,510 theaters), Lohman's performance met with wide critical acclaim and has been described as her "breakthrough role" by media sources. The following year, she appeared in Matchstick Men, directed by Ridley Scott. She starred with Nicolas Cage and Sam Rockwell, and though it was not a box office success either, Lohman continued to gain praise. Later that year, she appeared in Tim Burton’s Big Fish, which continued her trend of appearing in films of high acclaim, but little success.

She had no theatrical features in 2004, though she did voice the lead character in the re-dubbing of Nausicaä of the Valley of the Wind. In 2005 she appeared in Atom Egoyan's Where the Truth Lies. The film originally received an NC-17 rating for its graphic sexual content, and failed at the box office afterwards. Some critics (such as Roger Ebert) felt that she was well-suited for the role. Her next feature, The Big White, featured her alongside actors including Robin Williams, Holly Hunter and Tim Blake Nelson), but nevertheless went direct-to-video.

Lohman's next film was the drama Flicka, which was released on October 20, 2006. In the film, Lohman plays a 16-year-old girl who befriends a wild mustang. Lohman had never ridden a horse prior to filming and trained rigorously for a month. She said that she was "constantly thrown emotionally and physically" while working with the horses for this role. Flicka went on becoming a surprise hit in DVD market. She next played a recovering heroin addict in Things We Lost in the Fire. The actress has been signed to replace Oscar nominee Ellen Page in a new Sam Raimi horror film, Drag Me to Hell, that was set to begin filming on March 31, 2008. Lohman, who is frequently cast as a teenager, has said that she believes she "looks younger and acts younger" than her age.

• Drag Me to Hell (2009) (post-production) .... Christine
• Game (2009) (completed) .... Trace
  
• Beowulf (2007) .... Ursula
  ... aka Beowulf: An IMAX 3D Experience (USA: IMAX version)
  ... aka Beowulf: The IMAX Experience (USA: IMAX version)
• Things We Lost in the Fire (2007) .... Kelly
• Flicka (2006) .... Katy McLaughlin
• Delirious (2006) .... K'Harma Leeds
• Where the Truth Lies (2005) .... Karen
• The Big White (2005) .... Tiffany
  ... aka Grand blanc, Le (Canada: French title)
  ... aka The big White - Immer Ärger mit Raymond (Germany)
• Big Fish (2003) .... Sandra Templeton Bloom
• Matchstick Men (2003) .... Angela
• White Oleander (2002) .... Astrid Magnussen
  ... aka Weißer Oleander (Germany)
• "Pasadena" .... Lily McAllister (13 episodes, 2001-2002)
       - Don't It Always Seem to Go? (2002) TV episode .... Lily McAllister
       - A Lie Worth Fighting For (2002) TV episode .... Lily McAllister
       - The Truth Hurts (2002) TV episode .... Lily McAllister
       - A River in Egypt (2002) TV episode .... Lily McAllister
       - Someone to Talk To (2002) TV episode .... Lily McAllister
        (8 more)
• White Boy (2002) .... Amy
  ... aka Menace (USA: video title)
• Alex in Wonder (2001) .... Camelia Jameson
  ... aka Sex and a Girl (USA: video title (TV title))
• Delivering Milo (2001) .... Ms. Madeline
• "Tucker" .... McKenna Reid (3 episodes, 2000)
       - Everybody Dance Now (2000) TV episode .... McKenna Reid
       - Seth Green with Envy (2000) TV episode .... McKenna Reid
       - Pilot (2000) TV episode .... McKenna Reid