Struggling musician Peter Bretter is devastated when his actress girlfriend of five years, Sarah Marshall, abruptly breaks up with him. In an effort to heal his broken heart and escape their shared memories, Peter decides to take a solo trip to a luxurious Hawaiian resort. Upon arrival, he is shocked to discover that Sarah is staying at the same resort with her new rock star boyfriend, Aldous Snow. The coincidence forces Peter into awkward and painful interactions with the couple, exacerbating his heartache and embarrassment.

Trying to salvage his vacation, Peter resolves to ignore Sarah's presence and begins engaging with the other guests and staff at the resort. Among them, he meets a compassionate hotel employee, Rachel, who offers him kindness and distraction. As Peter bumbles through various resort activities, attempting to have fun and forge new friendships, he grapples with feelings of inadequacy and jealousy. His interactions with Sarah, Aldous, Rachel, and the quirky resort guests lead to comedic situations and personal reckonings, as he stumbles his way towards recovery from his emotional turmoil.