Andie Anderson (Kate Hudson) is a writer for the women’s magazine Composure as the “How to”, subject-matter expert. She is bored and wishes she could write about more serious topics. After Andie’s best friend Michelle (Kathryn Hahn) experiences yet another break-up, Andie is inspired to write a new article titled “How to Lose a Guy in 10 Days”; she will begin dating a man and drive him away within 10 days.
Simultaneously, advertising executive Benjamin “Ben” Barry (Matthew McConaughey) is looking to branch out from his usual remit of beer and sports campaigns, and lead a prestigious advertising campaign for a diamond company. At a bar, Ben’s boss, Phillip (Robert Klein) questions whether Ben has enough insight into the romance typically associated with diamonds, and in response Ben wagers he could make any woman fall in love with him. His manager accepts the wager and says that if he can achieve this before an event that will take place in 10 days, he will allow Ben to lead the diamond campaign. Ben’s rivals, Judy Spears and Judy Green (Michael Michele and Shalom Harlow), were at the Composure magazine offices earlier in the day and know about Andie’s task. Seeing Andie at the bar, they pick her as the woman to be romanced by Ben.
Ben and Andie meet and soon start their quests, neither revealing their true intentions. Andie works hard to drive Ben insane and make him break up with her in order to complete her article, but Ben continues to stick around in hopes of making her fall in love with him. Andie gets Ben knocked out in a movie theater by talking aloud while watching a film, rapidly moves her things into his apartment, acts overly possessive and clingy, ruins his 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.