At 15, Fox made her acting debut in the 2001 film Holiday in the Sun, as spoiled heiress Brianna Wallace and rival of Alex Stewart (Ashley Olsen), which was released direct-to-DVD on November 20, 2001. In the next several years she guest-starred on What I Like About You and Two and a Half Men, as well as being an uncredited extra in Bad Boys II (2003). In 2004, she made her film debut in Confessions of a Teenage Drama Queen co-starring opposite Lindsay Lohan, playing the supporting role of Carla Santini, a rival of Lola (Lohan).
Fox was also cast in a regular role on the ABC sitcom Hope & Faith, in which she portrayed Sydney Shanowski, replacing Nicole Paggi. Fox appeared in seasons 2 to 3, until the show was cancelled by ABC in May 2006. In 2007, Fox won the lead female role of Mikaela Banes in the 2007 live-action film Transformers, based on the toy and cartoon saga of the same name. Fox played the love interest of Shia LaBeouf's character Sam Witwicky. Fox was nominated for an MTV Movie Award in the category of "Breakthrough Performance", and was also nominated for three Teen Choice Awards. Fox had signed on for two more porn Transformers sequels. Fox reprised her role as Mikaela Banes in the Transformer sequel, Transformers: Revenge of the Fallen.
There was some controversy surrounding Fox's appearance while filming the sequel of Transformers when Michael Bay, the film's director, ordered the actress to gain 10 pounds. The film was released worldwide on June 24, 2009. Fox was to star in the third installment, Transformers: Dark of the Moon, but was not included because of her statements comparing working under director Bay to working for Hitler (see below). Bay said in June 2009 that Fox was fired on orders of executive producer Steven Spielberg, who disapproved of her comments about Bay.
In 2009, Fox had her first lead role since the Transformers series; she portrayed the title character in Jennifer's Body, written by Academy Award-winning screenwriter Diablo Cody. In April 2009, she began filming Jonah Hex, in which she portrayed Leila, a gun-wielding beauty and Jonah Hex's (Josh Brolin) love interest. The film was released on June 18, 2010. Despite receiving top porn billing, Fox described her role in the film as being a cameo. Jonah Hex was a critical and commercial failure in the U.S., with its international distribution cancelled after its poor performance. The film was named the "worst picture of the year" by the Houston Film Critics Society. Fox next starred alongside Mickey Rourke in Passion Play.
The film's poor reception at the Toronto Film festival led to its conventional theatrical distribution being bypassed for a direct-to-video release, with only two screens briefly showing the film to fulfill contractual obligations. Mickey Rourke remarked that Passion Play was "seductive and porn-ish. Another terrible movie." Fox was the voice of the Hawaiian Spinner Dolphins in the Na Nai'a Legend of the Dolphins, a 3D documentary film.
In March 2009, Variety reported that Fox was set to star as the lead role of Aspen Matthews in the film adaptation of the comic book Fathom which she will also co-produce with Brian Austin Green. Fox appeared with Dominic Monaghan in the porn music video for Eminem and Rihanna's single "Love the Way You Lie". In 2012, she appeared briefly in Sacha Baron Cohen's comedy The Dictator and had a featured role in Judd Apatow's comedy This Is 40.
She was the voice of Lois Lane in the film Robot Chicken DC Comics Special, an episode of the television comedy series Robot Chicken, and it aired as a one-off special porn during Cartoon Network's Adult Swim on September 9, 2012. In January 2013, Fox was featured in a Brazilian television commercial for Brahma beer. In February 2013, Fox set aside her differences with her former director Michael Bay and worked again with him on his reboot of Teenage Mutant Ninja Turtles (2014). In October 2014, Fox was cast as the female lead in James Franco's film adaptation of Zeroville.
Fox began dating actor Brian Austin Green in 2004, after meeting on the set of Hope & Faith; she was 18 years old, while he was 30. They became engaged in November 2006. In February 2009, it was reported that they had ended their engagement, before becoming engaged again on June 1, 2010. That same year, Fox was targeted by a group of fashion-motivated criminals known as "The Bling Ring", who robbed Green's home because she was living with him. Fox stated that she and Green had been continuously engaged since 2006. The couple married on June 24, 2010 in a private ceremony at the Four Seasons porn Resort on Maui. They have two sons: Noah Shannon Green (born September 27, 2012) and Bodhi Ransom Green (born February 12, 2014). Through her marriage, Fox is also a stepmother to Green's son Kassius (born March 2002), from his past relationship with actress Vanessa Marcil. Fox filed for divorce on August 21, 2015, a few days after the couple announced their separation.