Andie Anderson (Kate Hudson) is a writer who works for a magazine called Composure as the "How to..." girl. She is bored and wishes she could write more about important things, such as politics, economics, religion, poverty; stuff she cares about. She soon finds herself writing an article called "How to Lose a Guy in 10 Days". The idea comes about when Andie's friend, Michelle (Kathryn Hahn), experiences a minor breakdown after yet another break-up. Using her friend as inspiration, Andie reveals how she will actually start dating a guy and drive him away but "only using the classic mistakes women make".
At the same time, advertising executive Benjamin Barry (Matthew McConaughey) is striving for a pitch to advertise diamonds and explains to his boss and co-workers how "a woman in lust wants chocolate, a woman in love wants diamonds". When they question Ben's knowledge about love, Ben bets he could make any woman fall in love with him if he wanted to. If he can make any woman fall in love with him before the upcoming company ball, in just 10 days, he can head the advertising for the new diamond company.
Ben's rival co-workers, Judy Spears (Michael Michele) and Judy Green (Shalom Harlow), who were at Composure magazine earlier and are aware of Andie's new assignment, conspire to have Andie and Ben meet that night and start their quests. Fortunately, that night Andie and Ben happen to be in the same place and as Judy and Judy refer to Andie as "the blonde with the pretty smile", Ben thinks it is a done deal.
Neither Andie nor Ben reveals their true intentions. Andie works hard to make Ben break up with her in order to complete her article. However, Ben continues to stick around in hopes of making her fall in love with him. Andie goes on to get Ben knocked out at a chick flick, rapidly moves her things into his apartment, acts overly possessive and sensitive at all times, ruins boys' poker night for him and his friends, and takes him to a Celine Dion concert when he was under the assumption he was going to see a New York Knicks basketball game.
Ben stays with her despite everything, and after coming very close to breaking up they attend couples counseling, led by Andie's friend Michelle. They agree, as a solution to their "problems", to visit Ben's family in Staten Island for the weekend. While holidaying together, Ben and Andie begin to form a genuine bond, playing card games with the family, learning to ride Ben's motorcycle. Upon arrival home Ben even refers to Andie as "his girlfriend".
Andie tries to explain to boss Lana (Bebe Neuwirth) that she cannot continue writing and publishing this article as she has "really got to know this guy", but Lana remains insistent upon it. Around the same time, Andie and Ben go to the company ball together where Ben's boss, Phillip (Robert Klein), meets Andie and tells Ben that he "met her, she loves you, you win". Seeing Ben's good news, Spears and Green are instantly envious and set about to ruin it for their co-worker. They tell his close colleagues, Tony (Adam Goldberg) and Thayer (Thomas Lennon), Andie knew about the bet all along and was playing along to help Ben win. Almost instantly, Tony and Thayer rush to Andie's side and beg her to keep quiet, when they do not realize she is still blissfully unaware. Almost simultaneously, Andie's boss Lana - who is unaware of Ben's role in Lana's "How To" article - reveals Andie's true intentions to Ben.
Upon learning of Ben's bet, Andie attempts to humiliate Ben by getting on stage and telling all he has prepared a "special treat": to sing a song. In an attempt to leave, Ben reveals they have prepared a "duet" and instructs his friends to not let her leave the room. They go on to sing a poor version of Carly Simon's "You're So Vain", which they describe as "one of their personal favourites". They alternate singing the lyrics as:
A: "Ben Barry you're so vain, you probably think this song is about you, don't you, don't you! You fooled me to win a bet, you should feel ashamed". B: "Look, You took me to a god damn Celine Dion concert, you made me miss the big game". A: "Oh, Smart Guy's a rhymer, well do we want everybody to know your love making is lame". B: "Maybe because you named my penis, you named my penis, you named my penis after a dame."
They go their separate ways before Ben is shown Andie's article and encouraged to read it. She explains in it how she "lost the one man she ever fell for", and when he hears she quit her job at Composure and is on her way to Washington, D.C. for an interview, he chases her taxi and stops her. Once he accuses her of running away, they reveal their true feelings for each other and the film ends with Ben's instructing the taxi driver to return Andie's belongings to her home, and then they kiss.