In 2002, Jovovich starred in the horror/action film Resident Evil, released in the United States on March 15, 2002. Based on the CAPCOM video game series of same name, she portrayed Alice, the film's heroine who fights a legion of zombies created by the evil Umbrella Corporation. Jovovich had accepted the role of Alice because she and her brother had been fans of the video game franchise, saying "it was exciting for me just watching him play, I could sit for 5 hours and we would sit all day and play this game". Jovovich had performed all the stunts required in the film, save for a scene that would involve her jumping to a cement platform, which her management deemed too dangerous, and had trained in karate, kick-boxing and combat-training. The film was commercially successful, grossing $17 million on its opening weekend, and gaining $40 million domestically and $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, as opposed to previous characters, possessed similar qualities to the actress's own life.

In 2004, Jovovich reprised the role of Alice in the sequel to Resident Evil, Resident Evil: Apocalypse. The role required her to do fight training for three hours a day, in addition to the three months prior to filming in which she had "gun training, martial arts, everything". Apocalypse received even more negative reactions from the critics than the first film. Following the release of the film, Jovovich was unhappy with the results and director Alexander Witt's effort. She noted during an interview that year that her large action films take care of the commercial part of her career, while she acts in "independent little films that never come out" to appease her artistic side, and "It's a good balance". The following year, she was featured in Gore Vidal's faux trailer remake of Caligula, as Drusilla. In 2006, Jovovich's film, the science fiction/action thriller Ultraviolet, was released on March 3. She played the title role of Violet Song jat Shariff, a role that also involved heavily choreographed fight sequences and Gun Kata, a fictional martial art combining statistical analysis and gunplay. It was not screened for critics, but when reviewed, it was critically panned, grossing $31 million world wide. That year Jovovich also starred in .45, as Kat, the revenge driven girlfriend of an illegal gun dealer.

• The Winter Queen (2010) (in production) .... Amalia Bezhetskaya
• Keep Coming Back (2010) (pre-production) (rumored)
• The 4th Kind (2009) (post-production) .... Abbey
• A Perfect Getaway (2009) (completed) .... Cydney
  
• Resident Evil: Extinction (2007) .... Alice
  ... aka Resident Evil: Extinction (Germany)
• .45 (2006) .... Kat
• Ultraviolet (2006) .... Violet
• Trailer for a Remake of Gore Vidal's Caligula (2005) .... Druscilla
• Resident Evil: Apocalypse (2004) .... Alice
  ... aka Resident evil - L'apocalypse (Canada: French title)
• "King of the Hill" .... Serena (1 episode, 2002)
       - Get Your Freak Off (2002) TV episode (voice) .... Serena
• You Stupid Man (2002) .... Nadine
  ... aka Love Birds - Liebe auf den zweiten Blick (Germany)
  ... aka You Stupid Man (Germany)
• The House on Turk Street (2002) .... Erin
  ... aka No Good Deed (USA: DVD title)
• Resident Evil (2002) .... Alice
  ... aka Resident Evil (France) (Germany)
• Dummy (2002) .... Fangora
• Zoolander (2001) .... Katinka
  ... aka Zoolander (Germany)
• The Claim (2000) .... Lucia
  ... aka Maître de Kingdom Come, Le (Canada: French title)
  ... aka Rédemption (France)
• The Million Dollar Hotel (2000) .... Eloise