In 2006, Moore guest-starred in two episodes of Scrubs. The same year, she lent her voice to The Simpsons, playing Tabitha Vixx in the episode Marge and Homer Turn a Couple Play which aired in May. Moore also appeared in the parody American Dreamz, which was released in April 2006. In the film, she played a deranged contestant on a television series modeled after American Idol. Director Paul Weitz stated that he had Moore in mind for the role before she was cast, explaining that "there's something inherently sweet about Mandy; it makes it all the more interesting to see her in a villainess role". Moore has said that she enjoys playing mean-spirited characters but fears being typecast as a villain. American Dreamz opened at number nine at the U.S. box office, eventually totaling barely $7 million, and received mixed reviews; critic Owen Gleiberman of Entertainment Weekly, however, wrote that Moore and co-star Hugh Grant have a "wicked barbed chemistry" in their roles, while Variety's Robert Koehler said Moore's role was a "pitch-perfect study of a woman for whom a reality show is reality".

Later that year, in what ComingSoon.net's review described as a "surprisingly good performance", Moore voiced Nita, the heroine of the Disney animated sequel Brother Bear 2, which was released directly-to-DVD on August 29. She was also originally cast to appear in that year's ensemble film Bobby, but was replaced by Mary Elizabeth Winstead. Moore was on the cover of Cosmopolitan in May 2006, although she has expressed dissatisfaction with the cover's "racy" headlines.

Moore, citing her conservative upbringing, has expressed dissatisfaction with her appearance on a May 2006 cover of Cosmopolitan; the magazine's headline is "orgasms unlimited", which refers to an article unrelated to her. Ironically in her next movie, Because I Said So, co-starring Gabriel Macht, Lauren Graham and Diane Keaton, Moore's character describes in detail the feeling of an orgasm to her mother, Keaton's character. It was released on February 2, 2007 and received mixed reviews. In License to Wed, Moore portrays a young bride-to-be who has to complete a three-week prenup course before her wedding. Co-starring John Krasinski as her fiance and Robin Williams as a minister, the film was released on July 3, 2007 to mostly negative reviews.

• "How I Met Your Mother" .... Amy (1 episode, 2007)
       - Wait for It (2007) TV episode .... Amy
• License to Wed (2007) .... Sadie Jones
• Because I Said So (2007) .... Milly Wilder
• Dedication (2007) .... Lucy Reilly
• Brother Bear 2 (2006) (V) (voice) .... Nita
• "The Simpsons" .... Tabitha Vixx (1 episode, 2006)
       - Marge and Homer Turn a Couple Play (2006) TV episode (voice) .... Tabitha Vixx
• Southland Tales (2006) .... Madeline Frost Santaros
  ... aka Southland Tales (Germany: DVD title)
• American Dreamz (2006) .... Sally Kendoo
  ... aka American Dreamz (Australia)
• "Scrubs" .... Julie Quinn (2 episodes, 2006)
       - Her Story II (2006) TV episode .... Julie Quinn
       - My Half-Acre (2006) TV episode .... Julie Quinn
• Romance & Cigarettes (2005) .... Baby
• Racing Stripes (2005) (voice) .... Sandy
• Saved! (2004) .... Hilary Faye