Åkerman made her acting debut on the Canadian science fiction series Earth: Final Conflict in 1997, in a smaller role as a robot. She originally landed a role on an MTV pilot with Rachel McAdams, but the project was never picked up by the network. In 2000, she guest starred on Relic Hunter and had a smaller role in the American film The Skulls. The following year, she made appearances on the Canada-based series Doc and Twice in a Lifetime. In 2001, she moved to Los Angeles, California in hopes of pursuing a broader acting career. At first, she worked as a waitress and stayed at a friend’s house. In 2002, she received smaller role in the film The Utopian Society. The film was edited by Francesco Sondelli, the guitarist for alternative rock band Ozono. Sondelli asked Åkerman to help the band with song lyrics and later asked her to sing. Åkerman subsequently became the band’s singer, and they changed their name to The Petalstones. The band’s debut album, Stung, was released in August 2005, but Åkerman eventually left to focus on her acting career, admitting that she “actually can’t sing”. She described her singing as “sort of a self-made, self-taught, if-you-can’t-hit-the-note-scream-it kind of thing”.
In 2004, she got a small role in the film Harold & Kumar Go to White Castle, but considered moving back to Canada as most of her auditions failed. She was then cast in a supporting role as Juna on the HBO television series The Comeback, with Lisa Kudrow in the main role. Kudrow played a former sitcom star who tried to restart her career. Åkerman’s appearance on the show garnered media attention and resulted in her being offered more roles. A year later, she guest starred on an episode of Love Monkey and two episodes of Entourage. Before the Entourage episodes aired, she landed a role in the 2007 comedy film The Brothers Solomon. The film was a box office bomb and received largely critical reviews.
Åkerman signed up for a role opposite Ben Stiller in the comedy film The Heartbreak Kid, directed by the Farrelly Brothers, in 2006. She played Lila, the newly wedded wife of Stiller’s character. The film follows the couple’s honeymoon in Mexico, where Stiller’s character falls in love with another woman and realizes that the marriage was a mistake. A remake of the 1972 film of the same title, it was released in October 2007 to generally poor reviews, as critics deemed it “neither as daring nor as funny” as the directors’ earlier films. Åkerman’s performance garnered more positive reviews; Desson Thomson of The Washington Post called her a “fabulous comic partner” to Stiller, while Roger Moore of Times Herald-Record asserted that she had outperformed him. The film grossed $14 million in its opening weekend in the United States, and went on to gross $127 million globally.
In 2007, Åkerman joined the cast of 27 Dresses, a romantic comedy film directed by Anne Fletcher with Katherine Heigl in the lead role. The film follows Heigl’s character Jane, who has always been the bridesmaid and dreams of her own wedding. Åkerman played Jane’s sister Tess. The film was shot during the summer of 2007, and was released in January 2008 to weak critical reception as it was considered “clichéd and mostly forgettable”. The film was more successful commercially, with a gross of $160 million. Åkerman played the title role in Bye Bye Sally, a short film directed by Paul Leyden and based on Lisa Mannetti’s short story Everybody Wins. The film premiered at the 2009 Newport Beach Film Festival.