Composer Peter Bretter (Jason Segel) has spent five years idolizing his girlfriend, television star Sarah Marshall (Kristen Bell). While writing a Muppet-type Dracula musical, he's the guy left holding her purse in paparazzi photos and accidentally omitted from acceptance award speeches. Things take a twist when she breaks up with him, and Peter suddenly finds himself alone. After an unsuccessful bout of womanizing and an on-the-job nervous breakdown, he sees that not having Sarah may just ruin his life.

To clear his head, Peter takes an impulsive trip to Hawaii, where he is confronted by his worst nightmare: Sarah and her narcissistic and tragically-hip, new British-rocker boyfriend, Aldous (Russell Brand), are staying at his hotel. As he torments himself with the reality of Sarah's new life, he finds relief when flirting with Rachel (Mila Kunis), a beautiful resort employee whose laid-back approach tempts him to rejoin the world.