The same year she played supporting character, Mouse, in the independent film American Gun.
In 2006 Seyfried appeared in five episodes of Wildfire as Rebecca and had a lead role as Chrissy in the short film Gypsies, Tramps & Thieves, by writer-director Andrea Janakas.
She then starred in the dark fantasy historical romance Red Riding Hood (2011), the dystopian sci-fi thriller In Time (2011), the thriller Gone (2012), the musical drama film Les Misérables (2012), the biographical drama Lovelace (2013), and in the Seth Mac Farlane comedies A Million Ways to Die in the West (2014) and Ted 2 (2015). She played Joni Stafford on the ABC soap All My Children from 2002 to 2003.
In 2003, Seyfried auditioned to play the role of Regina George in Mean Girls; the role eventually went to Rachel Mc Adams.
In early March 2009 director Zack Snyder had tapped Seyfried to portray the lead role, Baby Doll, in Sucker Punch, Despite the reviews, Dear John became the first film to break up Avatar's box office reign at number one at the United States box office and grossed US$80 million in the US theatrically and US$115 million worldwide.
Later in 2010, Seyfried starred in the romantic-comedy film Letters to Juliet, based on the book by Lise and Ceil Friedman, which was released to mixed reviews and was a box office success, generating US$80 million worldwide.
Seyfried was also nominated for Choice Movie Actress Romantic Comedy for Letters to Juliet.
Seyfried played the starring role of Valerie in Catherine Hardwicke's Red Riding Hood; it was released on March 11, 2011, to mostly negative reviews, but earned US million worldwide on a US million budget.
While she was initially considered to play the lead role of Cady Heron, played by Lindsay Lohan, the producers of the film decided that Seyfried should play Karen Smith, Regina's dim-witted "Plastic" friend and sidekick.
Seyfried's performance in the film earned her, along with Lohan, Lacey Chabert, and Mc Adams, an MTV Movie Award in the category of "Best On-Screen Team".
She does the floral arrangements for Rachel’s (Piper Perabo) wedding, and the two women share a long look as Rachel walks down the aisle.
Although Rachel marries her husband as planned, over the course of the movie the two women become friends and explore their unexpected chemistry.
In 2005, Seyfried played the lead character, Samantha, a role written by director Rodrigo García specifically for her, in one of the nine parts of the film Nine Lives, composed of nine short films with different themes and an ensemble cast.