Paquin returned to worldwide prominence with her role as Rogue in the blockbuster X-Men movie in 2000, its sequel X2: X-Men United in 2003, and its third installment X-Men: The Last Stand in 2006.

In the summer of 2006, she completed filming Blue State. She executive-produced the film, the film having been made by Paquin Films, a production company formed by both her and her brother, Andrew Paquin. In November 2006, she completed Margaret. This film is now scheduled for release in 2009, according to imdb.com.

In 2007, Paquin received an Emmy Award nomination for Supporting Actress In A Miniseries Or A Movie for her role as Elaine Goodale in the HBO's made-for-TV movie Bury My Heart at Wounded Knee, based on Dee Brown's bestseller. She also received Golden Globe and Screen Actors Guild Award nominations in similar categories.

In 2008, Paquin appeared as Sookie Stackhouse in the HBO series True Blood, her first role in a TV series. The show is based on The Southern Vampire Mysteries series of novels by Charlaine Harris. Paquin won a Golden Globe for Best Actress in a Television Drama Series for her role in the show, and also won a Satellite Award in a similar category. A second season of the show has been commissioned, and is currently in production. It is scheduled to air in May 2009.

CBS has announced that Paquin will play Irena Sendler, a Polish woman hailed as a heroine of the Holocaust, in Miss Irena's Children, a TV film biopic based on the book Mother of the Children of the Holocaust: The Irena Sendler Story, by Anna Mieszkowska. The film has been made in Latvia, and will be a Hallmark Hall of Fame presentation for the network.