The film revolves around newlyweds Carl and Molly Peterson (Dillon and Hudson). After Carl's best man and friend Randolph Dupree (Wilson) loses his job and apartment, the couple allow him to move in but Dupree inevitably overstays his welcome.
Molly (Kate Hudson) and Carl (Matt Dillon) are preparing for their wedding day in Hawaii, until Carl's friend Neil (Seth Rogen) interrupts to say that Randolph Dupree (Owen Wilson) got lost. They drive off together to pick up Dupree, who appeared to have hitched a ride with a light plane after landing on the wrong island. A day before the wedding, Molly's father, Bob Thompson (Michael Douglas), who is also CEO of the company that Carl works for, makes a toast with humorous remarks at Carl's expense, foreshadowing a conflict between the two. Later at a pre-celebration at a bar, Carl neglects Dupree to be with Molly. Carl and Dupree later make up on the beach, as Dupree apologizes for laughing at Molly's father's jokes. Carl and Molly get married. When Carl returns to work, at Molly's father's Thompson Land Development, he is surprised to find that Mr. Thompson has promoted him to be in charge of a design he proposed, though it had been altered somewhat.
Mr. Thompson makes absurd requests which proceed to get worse, starting with Thompson's drastic reimagining of Carl's new architecture project and that Carl get a vasectomy to prevent any future children with his daughter. Before returning home to celebrate his promotion with Molly, Carl stops by the bar, where he finds Neil and Dupree. After Neil leaves, Dupree reveals that he has financial problems, such as being evicted from his home and losing his job and car. Carl and Molly take Dupree into their home, though clearly they are frustrated as he is disruptive and messy. Molly sets up Dupree with a woman at her work, a primary school, who is a Mormon librarian. Dupree agrees, though Molly is shocked to find them having graphic sex when she comes home from dinner. Romantic candles burn down the front of the living room, and Dupree is kicked out.
Meanwhile, Carl is being continually stressed out from work, though he and Molly find time to go out for dinner. On the way back they find Dupree sitting on a bench in heavy rain with his belongings. Dupree reveals that the librarian had just dumped him. Feeling pity, Molly insists they take him back in. Dupree apologizes for being disruptive and agrees to mend his ways. The next day, Dupree makes amends, refurbishing the living room, and doing Carl's thank-you letters, as well as making friends with kids from the block. Dupree cooks a large dinner for Molly and Carl, though Carl is late again, so Molly and Dupree start without him. When Carl finally shows up, he is a little jealous that they were having dinner together, and have a fight. Carl kicks Dupree out, suspecting an affair, which shocks Dupree. The following night, Mr. Thompson comes over for dinner. Dupree attempts to sneak back in to their home to get some of his belongings, but fails and falls off the roof. He is found outside and is invited in for dinner.
After Mr. Thompson takes a liking to Dupree and asks him to go fishing with him, it enrages Carl because - even though he doesn't like fishing - it's Mr. Thompson's way of approving someone. Carl's fury boils over as he then imagines Dupree hanging out with Mr. Thompson and engaging in sex with Molly, causing Carl to jump across the table and attempting to strangle Dupree; Mr. Thompson hits Carl over the head with a candlestick shortly after. After returning from the hospital with a neck brace, Dupree and Molly confront Mr. Thompson about what he really thinks of his new son-in-law, while Carl had left. The next morning, Dupree gets all the local kids to search for Carl. Dupree eventually finds Carl in the bar, and convinces him to chase after Molly. Dupree helps Carl break into Mr. Thompson's office and confront him while Dupree himself distracts and evades a Samoan guard. Carl and Mr. Thompson finally reach an understanding and Thompson admits to his agenda of insulting Carl. Dupree and Carl return to the house, where Carl and Molly reunite, Carl apologizing, and agree to work it all out. Glad that he did his job, Dupree celebrates by leaping into the air with joy, until he falls to ground.
All turns out well, with Dupree becoming a motivational speaker, Carl and Molly spending more time with each other, and Mr. Thompson accepting Carl as family. In a post-credits scene, famed bicyclist Lance Armstrong is seen reading Dupree's motivation book, 7 Different Kinds of Smoke: Living, Loving, and Finding your Inner "-ness".Owen Wilson as Randolph "Randy" Dupree
Kate Hudson as Molly Thompson Peterson
Matt Dillon as Carl Peterson
Michael Douglas as Bob Thompson
Seth Rogen as Neil
Amanda Detmer as Annie
Ralph Ting as Toshi
Todd Stashwick as Tony
Bill Hader as Mark
Lance Armstrong as himself
Billy Gardell as the bar keep
Harry Dean Stanton as Curly (uncredited)
Pat Crawford Brown as Aunt Kathy
Sidney S. Liufau as Paco
The film's production budget totalled $54 million. Composer Rolfe Kent scored the film, and at the very last minute—a mere week before the press screenings—his score was replaced by one written by Theodore Shapiro. The scene that has Dupree arriving by plane on the wrong island was shot in the same valley as Jurassic Park. In the special features of the film, there is a different version trailer of You, Me and Dupree where in the trailer Dupree and Molly are married and Carl moves in. The DVD release of the film also contains a re-cut trailer horror/thriller version of the film.
The film received mostly negative reviews from critics. Rotten Tomatoes gives the film a 21% rating based reviews from 165 critics. The site's consensus is "a rather generic entry into the arrested development subgenre, with themes borrowed from other more successful and funnier films. Dupree wears out its welcome."
Roger Ebert gives the film 2 stars out of 4, and compares the film to many other predecessors, suggesting Dupree is a 'descendant' of Dignan also played by Wilson in Bottle Rocket, and that the film is at times like a version of Fatal Attraction, but criticizes the film for never properly deciding if Dupree is merely unlucky or actually manipulative. Ebert describes the film as having an "Idiot Plot" requiring characters to behave in unnatural ways for laughs or to force the plot forward, the comedy equivalent of "Don't go down to the cellar!" in horror movies.
On release for 84 days, the film grossed $75,628,110 at the North American domestic box office, and in addition earned $54,803,258 in international markets, for a worldwide total of $130,431,368.
The film's title caused a minor stir as the uncommon name, Dupree, is the same as the title character in the Steely Dan song "Cousin Dupree" from their 2000 album, Two Against Nature which also concerns a ne'er-do-well relative who becomes a problem houseguest. Steely Dan founders, Donald Fagen and Walter Becker wrote a somewhat tongue-in-cheek letter to actor Owen Wilson's brother Luke Wilson about the apparent appropriation of their character's name. The duo invited the elder Wilson to make up for the "theft" of their character's name by coming on stage with them at one of their concerts to apologize to the band's fans. Owen Wilson gave a tongue-in-cheek response to the letter, stating in a press conference, "I have never heard the song 'Cousin Dupree' and I don't even know who this gentleman, Mr. Steely Dan, is. I hope this helps to clear things up and I can get back to concentrating on my new movie, HEY 19."