Shannyn returned to film in 2005, by starring in the direct-to-video low-budget horror film Devour, alongside Jensen Ackles and William Sadler. Next, she had small roles in the films Undiscovered and Kiss Kiss Bang Bang. Undiscovered was a box-office and critical failure, but Kiss Kiss Bang Bang performed well at the box office, grossing more than $17,000,000 and was significantly praised by critics. She also appeared alongside Kate Winslet, Jack Black, Cameron Diaz, and Jude Law in Nancy Meyers's 2006 romantic-comedy The Holiday. The film was mainly aimed toward women, and it received positive reviews from critics. In 2006, Sossamon was cast as the female lead in the independent film Wristcutters: A Love Story opposite Patrick Fugit, Tom Waits, and Will Arnett. Wristcutters revolved around two characters who fell in love in purgatory after committing suicide. Its interesting plot gained the film a lot of attention. The film was shown at both The Sundance Film Festival and The Seattle International Film Festival Awards in 2006. Autonomous Films picked it up for distribution, and it was released on March 25, 2008, to extremely positive reviews. It was nominated for several awards including Sundance's Grand Jury Prize, two Independent Spirit Awards, the Humanitas Prize.

Sossamon was next cast in Courteney Cox's dark drama series Dirt on FX. She starred as Kira Klay, a celebrity who, after realizing that she is pregnant, kills herself. She then appears in visions to a schizophrenic photographer. Shannyn appears in five episodes in the first season. She then starred in the horror film Catacombs alongside singer Pink. It was FEARnet and Lions Gate Entertainment's first film collaborating. It was first released in 2007 in several countries including Italy, Japan and Mexico, but it wasn't released in the United States until 2008. It was filmed in early 2005, but its release was delayed for more than two and a half years for unknown reasons.

Next, Sossamon signed on as a series regular on CBS's vampire drama Moonlight. The series began airing on September 28, 2007, and was watched by 8.54 million viewers. CBS ordered a 16-episode first season, but over the season, viewership decreased to around 7.5 million viewers. The series had a very large fan base, but despite fans' efforts, CBS canceled the series after the first season. Her next project, One Missed Call, was a remake of the Japanese horror film Chakushin Ari. The film also stars Ed Burns, Azura Skye, Margaret Cho, and Ray Wise. The film received extremely negative reviews from critics but was considered a major box-office success, grossing more than $42,000,000 worldwide. It was also considered a success on DVD and Blu-Ray, generating sales of more than $25,000,000 since its release on April 22, 2008. In 2008, Sossamon appeared with George Clooney in the commercial "A Beautiful Race" for the company Martini. Her next two films—The Heavy and Life is Hot in Cracktown—are set to be released in late 2008 or 2009.

• How to Make It in America (2009) (TV) (pre-production) (rumored) .... Gingy
• Life Is Hot in Cracktown (2009) (completed) .... Concetta
  
• The Heavy (2008) .... Claire
• "Moonlight" .... Coraline / ... (10 episodes, 2007-2008)
       - Sonata (2008) TV episode .... Coraline
       - What's Left Behind (2008) TV episode .... Coraline
       - The Mortal Cure (2008) TV episode .... Coraline
       - Sleeping Beauty (2007) TV episode .... Coraline
       - Fleur De Lis (2007) TV episode .... Coraline / Morgan
        (5 more)
• One Missed Call (2008) .... Beth Raymond
  ... aka Don't Pick Up the Cell Phone! (Australia)
  ... aka Tödlicher Anruf (Germany)
• "Dirt" .... Kira Klay (5 episodes, 2007)
       - Ita Missa Est (2007) TV episode .... Kira Klay
       - What to Expect When You're Expecting (2007) TV episode .... Kira Klay
       - Ovophagy (2007) TV episode .... Kira Klay
       - Blogan (2007) TV episode .... Kira Klay
       - Pilot (2007) TV episode .... Kira Klay
• Catacombs (2007) .... Victoria
• The Holiday (2006) .... Maggie
• Wristcutters: A Love Story (2006) .... Mikal
  ... aka Pizzeria Kamikaze (International: English title: informal title)
  ... aka Pizzerija Kamikaze (Croatia)
• Undiscovered (2005) .... Josie
  ... aka Newcomer - Tausche Ruhm gegen Liebe (Germany)
• The Double (2005) .... Melanie
• Devour (2005) .... Marisol
• Kiss Kiss Bang Bang (2005) .... Pink Hair Girl
• Chasing Ghosts (2005) .... Taylor Spencer
• I Hate You (2005) .... Jo
• "Law & Order: Special Victims Unit" .... Myra Denning (1 episode, 2004)
  ... aka Law & Order: SVU (USA: promotional abbreviation)
  ... aka Special Victims Unit (New Zealand: English title)
       - Doubt (2004) TV episode .... Myra Denning
• The Order (2003) .... Mara Sinclair
  ... aka The Sin Eater (Australia) (Singapore: English title) (UK) (USA: working title)
  ... aka Sin Eater - Die Seele des Bösen (Germany)
• Wholey Moses (2003) .... Max
• The Rules of Attraction (2002) .... Lauren Hynde