In 2002, Jovovich starred in the horror-action film Resident Evil, released in the United States on March 15, 2002 and based on the CAPCOM video game series of the same name. She portrayed Alice, the film's heroine, who fights a legion of zombies created by the Umbrella Corporation. Jovovich had accepted the role because she and her brother Marco had been fans of the video game franchise. Jovovich had performed all the stunts required in the film, except for a scene that would involve her jumping to a cement platform, which her management deemed too dangerous, and had trained in karate, kickboxing, and combat-training. The film was commercially successful, grossing US$17 million on its opening weekend; it eventually made US$40 million domestically and US$102 million worldwide. Later, she portrayed the manipulative gang wife Erin in No Good Deed (2002), Nadine in the romantic comedy You Stupid Man (2002), punk rocker Fangora ("Fanny") in Dummy (2003), and provided a guest voice on the television series King of the Hill. The role of Fangora in Dummy allowed Jovovich to act in film with Oscar-winning Adrien Brody, who was a friend prior to filming. Jovovich found it easy to identify with this role because she felt Fangora possessed similar qualities to the actress' own life.
Jovovich has contributed tracks to several of her film soundtracks, including The Million Dollar Hotel (2000) and Dummy (2002), and has also provided songs for the soundtracks of films in which she has not acted such as Underworld (2003) produced by musician Danny Lohner who was the bass player in Nine Inch Nails for many years. Her song "The Gentlemen Who Fell" was featured on The Rules of Attraction soundtrack in 2002. In 2001, Jovovich was one of many celebrities whose vocals were featured in a cover of "We are Family" to raise money for the American Red Cross. She has appeared as guest vocalist on the song "Former Lover" on Deepak Chopra's album, A Gift of Love II: Oceans of Ecstasy (2002) and Legion of Boom (2004) by The Crystal Method.
Jovovich was said to be designer Miuccia Prada's muse in 2002; a 2003 article claimed she was Gianni Versace's "favourite supermodel". In 2004, Jovovich topped Forbes magazine's "Richest Supermodels of the World" list, earning a reported $10.5 million, and in 2006, Jovovich was picked up by Mango, a Spanish clothing line, as their new spokesmodel and is featured in their advertising campaigns; she can also be seen in adverts for Etro. She has said that "Modeling was never a priority" and that the money she earns enables her "to be selective about the creative decisions [she] make[s]".