In 2000, Larter starred in the teenage audience aimed horror film Final Destination as the "final girl" Clear Rivers. The following year in 2001, she appeared in the comedy Legally Blonde with Reese Witherspoon, western American Outlaws with Colin Farrell and the Kevin Smith film Jay and Silent Bob Strike Back. That year as well, Larter performed in the stage play The Vagina Monologues in New York City. The next year in 2002, Larter was ranked #40 in Stuff magazine's "102 Sexiest Women in the World". In 2003, Larter reprised her role as Clear Rivers in the sequel to Final Destination, Final Destination 2. In 2005, Larter appeared in the independent film Confess and the romantic comedy A Lot Like Love alongside Amanda Peet and Ashton Kutcher.

2006 saw Larter in the biographical film Crazy based on guitarist Hank Garland. As of September 2006, Larter has been portraying Niki Sanders on the NBC Emmy Award-nominated science fiction drama television series Heroes, created by Tim Kring. The show includes an ensemble cast including Hayden Panettiere, Milo Ventimiglia, Leonard Roberts, Masi Oka and Greg Grunberg. Larter's character Niki Sanders, who is a wife and mother, is a former internet stripper from Las Vegas who exhibits superhuman strength and an alternate personality who goes by the name of Jessica. After completing half its first season, Heroes had already collected an assortment of honors and accolades, and Larter had been nominated for "Best Supporting Actress" for the 33rd Saturn Awards. As of the third season, Larter portrays a new character, Tracy Strauss.

In 2007, Larter starred in the Bollywood Marigold as the title character alongside Salman Khan, which was released in August. She also joined the cast of the popular film franchise Resident Evil: Extinction portraying the character Claire Redfield in the horror film with Milla Jovovich. Her role sent her to Mexicali, Mexico for filming from May to late July in which she also dyed her hair a light red for the film. Larter explains on her character Claire, "She became the leader of this convoy. She's incredibly strong, patient. I think she serves a role for everyone within this convoy, let it be a mother to someone, a buddy, a best friend." Larter also attended the 2007 Comic Con International, her second appearance at the event, to promote the film, which was released in theaters on September 21, 2007. This year as well, she will appear in the comedy Homo Erectus. Larter was also featured as #6 in Maxim's Hot 100 for 2007.

In an interview for Resident Evil: Extinction, Larter had expressed interest in producing films in the future, saying, "I definitely have many ideas and different avenues that I want to take as my career goes on." Larter has been revealed to be part of the cast of When Angels Fall, a film where 7 demons, each representing one of the deadly sins, are unleashed upon the world and enact their biblical vengeance for being banished to a prison-like dimension, it has been revealed that she will play Lustacia, the queen of lust and seduction. In March 2008, it was announced that Larter would star opposite Beyonce Knowles and Idris Elba in the Screen Gems-produced film Obsessed, about an office worker (Elba) whose marriage to Knowles' character is threatened by the aggressive interests of a co-worker, to be portrayed by Larter. Shooting began in the summer of 2008. "Obsessed" is slated to be released in April of 2009.

• Obsessed (2009) (completed) .... Lisa Sheridan
  
• "Heroes" .... Niki Sanders / ... (39 episodes, 2006-2008)
       - Chapter Thirteen 'Dual' (2008) TV episode .... Tracy Strauss
       - Chapter Twelve 'Our Father' (2008) TV episode .... Tracy Strauss
       - Chapter Ten 'The Eclipse Part 1' (2008) TV episode .... Tracy Strauss
       - Chapter Nine 'It's Coming' (2008) TV episode .... Tracy Strauss
       - Chapter Seven 'Eris Quod Sum' (2008) TV episode .... Tracy Strauss
        (34 more)
• Crazy (2007/I) .... Evelyn Garland
• Resident Evil: Extinction (2007) .... Claire
  ... aka Resident Evil: Extinction (Germany)
• Marigold (2007) .... Marigold Lexton
  ... aka Marigold (India: Hindi title: dubbed version)
• Homo Erectus (2007) .... Fardart
  ... aka National Lampoon's The Stoned Age (USA: DVD title)
• Confess (2005) .... Olivia Averill
• A Lot Like Love (2005) .... Gina
• Three Way (2004) .... Isobel Delano
  ... aka 3-Way (USA: DVD box title)
  ... aka Three Way (Australia: DVD box title)
• Final Destination 2 (2003) .... Clear Rivers
  ... aka Destination Ultime 2 (Canada: French title)
• Jay and Silent Bob Strike Back (2001) .... Chrissy
• American Outlaws (2001) .... Zerelda 'Zee' Mimms
• Legally Blonde (2001) .... Brooke Taylor Windham
• Final Destination (2000) .... Clear Rivers
  ... aka Destination ultime (Canada: French title)