Andie Anderson, an aspiring journalist working for a women's magazine, is tired of writing fluff pieces. Seeking to tackle more serious topics, she pitches an unorthodox article idea to her editor: "How to Lose a Guy in 10 Days," where she will start dating a man and then drive him away using common mistakes women make in relationships. The goal is to document her steps and prove her thesis for the magazine's readers. Andie sets out to find her unsuspecting subject for this social experiment, looking for someone she can quickly entangle in a relationship and just as quickly drive away.

Ben Barry, a confident advertising executive, is an ambitious charmer who's equally tired of frivolous encounters and is focused on landing a major diamond account at work. He enters a bet with his boss: if he can make a woman fall in love with him in 10 days, he'll get the account, believing his marketing skills make him irresistible to women. Coincidentally, Andie and Ben cross paths, unwittingly becoming the perfect candidates for each other's schemes. As Andie employs increasingly brazen tactics to sabotage their burgeoning relationship, Ben counters with charm and persistence, unbeknownst to them both that they are effectively working against their own personal goals. Their careers hang in the balance as the 10-day deadline approaches, with neither aware of the other's hidden agenda.