Duff's first role in a theatrical motion picture was in Human Nature (2002), an independent film shot before Lizzie McGuire and first shown at the Cannes and Sundance film festivals. Written by Charlie Kaufman and directed by Michel Gondry, the film follows a female naturalist, played by Patricia Arquette. Duff played the younger version of Arquette's character.

Duff subsequently starred opposite Christy Carlson Romano and Gary Cole in the Disney Channel television film Cadet Kelly (2002), which became the network's most watched program in its nineteen-year history. Her first major role in a feature film was in Agent Cody Banks with Frankie Muniz in 2003. The film was successful enough to spawn a sequel, in which Duff did not participate. Later that year Duff played one of the twelve children of Steve Martin and Bonnie Hunt in the family film Cheaper by the Dozen, which remains her highest grossing film. She reprised her role in the sequel, Cheaper by the Dozen 2 (2005), which failed to be as financially successful as the original film and was panned by critics.

In 2004 Duff starred in the romantic comedy A Cinderella Story, an update of Charles Perrault's fairy tale Cinderella. The film became a moderate box office hit, grossing a total of $74,628,141 worldwide on a budget of just $19,000,000. The film was heavily panned, with the Las Vegas Weekly writing: "Effortlessly combining Duff's bad acting and bad singing with bad writing and bad direction, Raise Your Voice is an insulting waste of time that begs to be silenced." Reviews were, by and large, negative to Duff's vocals (several critics pointed out what appears to be her digitally enhanced voice) and indifferent towards her acting performance. The film received a muted reception at the box office, and is Duff's least successful film commercially, with total theater receipts of just $13,573,284. Duff received her first Razzie nomination for her role in Raise Your Voice and A Cinderella Story.

In The Perfect Man (2005) she played the oldest daughter of a divorced woman (Heather Locklear), who moves to New York City as she desperately searches for love. Reviews were mostly negative and the film disappointed at the box office, grossing a mere $19,770,475 globally.That year, Duff was again nominated for a Razzie Award, for both The Perfect Man and Cheaper by the Dozen 2. The 2006 satirical comedy Material Girls again disappointed, grossing only $14,189,525 worldwide. The Martha Coolidge-directed film, co-produced by Madonna's independent film production company Maverick Entertainment, starred Duff and her real-life sister Haylie Duff as wealthy siblings who must fight to reclaim their fortune following a scandal. For the film, Duff was nominated for another two Razzie awards on January 24, 2007.

The Duff sisters are due to lend their voices to the computer animated comedy Foodfight!, which Lions Gate Films is to distribute in 2007. The film's director, Larry Kasanoff, said that he is "absolutely thrilled to have the Duff sisters as part of the cast." Duff is currently slated to star opposite John Cusack in Brand Hauser, due for release in late 2007. The film is set in a futuristic country and Duff and Cusack have completed filming it in Bulgaria. Duff plays a European pop star named Yonica. Duff pushed back her fifth studio album so that she had ample time to work on the movie.