Wilson starred in the 2000 comedy action film Shanghai Noon alongside Jackie Chan. The film grossed nearly $100 million worldwide. His fame continued to rise after starring alongside Ben Stiller and Will Ferrell in the 2001 film Zoolander. Gene Hackman reportedly took notice of Wilson’s performance in Shanghai Noon and recommended the actor to co-star in the 2001 action film Behind Enemy Lines. Also in 2001, Wilson and Anderson collaborated on their third film, The Royal Tenenbaums, a financial and critical success. The film earned the writing team an Academy Award nomination for Best Original Screenplay.
Wilson returned to the buddy-comedy genre in 2002 with the action comedy I Spy, co-starring Eddie Murphy. This big-screen remake of the television series did not perform well at the box office. He made a cameo appearance in the Girl Skateboards video Yeah Right! in 2003. He then reunited with Chan to make Shanghai Knights (2003), and co-starred in the film remake of the 1970s television series Starsky & Hutch (2004). Due to his busy schedule as an actor and an ongoing sinus condition, Wilson was unavailable to collaborate on the script for Wes Anderson’s fourth feature film, The Life Aquatic with Steve Zissou. The 2004 film was ultimately co-written by filmmaker Noah Baumbach. However, Wilson did star in the film as Bill Murray’s would-be son, Ned Plimpton; a role written specifically for him.In 2004, he and his brother Luke played the Wright brothers in the 2004 film Around the World in 80 Days
Wilson partnered with Vince Vaughn in the 2005 comedy film Wedding Crashers, which grossed over $200 million in the US alone. Also in 2005, Owen collaborated with his brothers in The Wendell Baker Story, written by Luke and directed by Luke and Andrew In 2006, Wilson voiced Lightning McQueen in the Disney/Pixar film Cars, starred in You, Me and Dupree with Kate Hudson, and appeared with Stiller in Night at the Museum as cowboy Jedediah.
Wilson has starred with Ben Stiller in twelve films, including The Cable Guy (1996), Permanent Midnight (1998), Meet the Parents (2000), Zoolander (2001), The Royal Tenenbaums (2001), Starsky & Hutch (2004), Meet the Fockers (2004), Night at the Museum (2006), and the sequels Night at the Museum 2: Battle of the Smithsonian (2009), Little Fockers (2010), Night at the Museum: Secret of the Tomb (2014) and Zoolander 2 (2016.
Wilson appeared in another Wes Anderson film, The Darjeeling Limited, which screened at the 45th annual New York Film Festival, the Venice Film Festival and opened September 30, 2007, co-starring Jason Schwartzman and Adrien Brody.Wilson next starred in the Judd Apatow comedy, Drillbit Taylor, released in March 2008. He appeared in a film adaptation of John Grogan’s best-selling memoir, Marley & Me (2008), co-starring Jennifer Aniston.
He also starred in The Darjeeling Limited with Adrien Brody and Jason Schwartzman, which was selected for a DVD and Blu-ray release by The Criterion Collection in October 2010.He provided the voice for the Whackbat Coach Skip in Wes Anderson’s Fantastic Mr. Fox. He starred in the film The Big Year, an adaptation of Mark Obmascik’s book The Big Year: A Tale of Man, Nature and Fowl Obsession. The film was released in October 2011 by 20th Century Fox, and co-starred Jack Black, JoBeth Williams, Steve Martin and Rashida Jones.