Her first significant acting job was a guest role in the NBC prime-time drama ER, which remains one of her favorite roles: Fanning subsequently had several guest roles on television series, including CSI: Crime Scene Investigation, The Practice, and Spin City.She also portrayed the title characters of Ally Mc Beal and The Ellen Show as young girls.

Fanning followed with more mature roles, playing Lewellen in Hounddog (2007), Lily in The Secret Life of Bees (2008), the eponymous character in Coraline (2009), Cherie Currie in The Runaways (2010) and Jane Volturi in The Twilight Saga (2009–12).

Throughout the 2010s, she continued appearing in independent productions such as the dramas Now Is Good (2012) and Night Moves (2013), the comedy-drama Very Good Girls (2013), and the biographical film Effie Gray (2014).

While promoting her role in Dreamer, Fanning became a registered member of Girl Scouts of the USA at a special ceremony, which was followed by a screening of the film for members of the Girl Scouts of the San Fernando Valley Council.

Fanning then went on to star in War of the Worlds, starring alongside Tom Cruise.

In 2002, director Steven Spielberg cast Fanning in the lead child role of Allison "Allie" Clarke/Keys in the science fiction miniseries Taken.

By this time, she had received positive notices from several film critics, including Tom Shales of The Washington Post, who wrote that Fanning "has the perfect sort of otherworldly look about her, an enchanting young actress called upon ...

Released in reverse order (War in June 2005 and Dreamer in the following October), both films were a critical success.

Fanning moved straight to another film without a break: Charlotte's Web, which she finished filming in May 2005 in Australia, and premiered on December 15, 2006.

She rose to prominence at the age of seven for her performance as Lucy Dawson in the drama film I Am Sam (2001), for which she received a Screen Actors Guild Award nomination at age eight, making her the youngest nominee in SAG history.

Fanning played major roles in the films Uptown Girls (2003), The Cat in the Hat (2003), Man on Fire (2004), War of the Worlds (2005), Dreamer (2005), and Charlotte's Web (2006).

In 2001, Fanning was chosen to star opposite Sean Penn in the movie I Am Sam, the story of a mentally challenged man who fights for the custody of his daughter (played by Fanning).