
At the age of 16, Theron traveled to Milan, Italy, on a one-year modeling contract, after winning a local competition. She went to New York with Pauline's Model Management. She decided to remain after her contract ended, attending the Joffrey Ballet School, where she trained as a ballet dancer. A knee injury closed this career path when Theron was 19.
Unable to dance, Theron flew to Los Angeles on a one-way ticket her mother bought her. During her early months there, she went to a bank to cash a check her mother had sent her to help with the rent. When the teller refused to cash it, Theron immediately started a shouting match with her. Afterwards, a talent agent in line behind her handed her his business card and subsequently introduced her to some casting agents and also an acting school. She later fired him as her manager after he kept sending her scripts for films similar to Showgirls and Species. After eight months in the city, she was cast in her first film part, a non-speaking role in the direct-to-video film Children of the Corn III (1995). Larger roles in widely released Hollywood films followed, and her career skyrocketed in the late 1990s with box office successes like The Devil's Advocate (1997), Mighty Joe Young (1998), and The Cider House Rules (1999). She glossed the cover of the January 1999 issue of Vanity Fair as the "White Hot Venus".


In 2005, Theron portrayed Rita, Michael Bluth's (Jason Bateman) love interest, on the third season of Fox's critically-acclaimed television series Arrested Development. She also received Golden Globe and Emmy nominations for her role of Britt Ekland in the 2004 HBO movie The Life and Death of Peter Sellers.
In 2007, Esquire named her the Sexiest Woman Alive.

On November 10, 2008, TV Guide reported that Theron will star in the film adaptation of The Danish Girl alongside Nicole Kidman. Theron will play Gerda Wegener, wife of Einar Wegener/Lili Elbe (Kidman), the world's first known person to undergo sex reassignment surgery. In October 2009, Theron was cast to star in a sequel to the Mad Max films, titled Mad Max: Road Fury, which will start filming in Aust 2010.