The film begins with the clumsy Valerie Highsmith arriving at an airport in Puerto Vallarta. Eager to inform her father, a wealthy businessman, of her arrival, she recklessly leans on the balcony railing, leading to a fall several stories onto a canvas below. Soon after, while wandering the streets, she is knocked unconscious by a group of thieves and loses her memory. In a twist of fate, a local criminal named Frank Grimes takes her from her hotel.
Meanwhile, a psychologist named Monosoff, aware of Valerie's notoriously bad luck, convinces her father to send Eugene Proctor, an accountant himself plagued by misfortune, to locate her. He is teamed up with Raymond Campanella, a determined investigator whose patience is tried by Eugene's constant blunders.
Their trip to Mexico spirals into disaster as they face a myriad of unfortunate events, including broken luggage, subpar accommodations, and bar fights. They eventually learn from local police that Valerie's last known associate was none other than Frank Grimes. In a desperate bid, Eugene attempts to seek answers from a local prostitute, who promptly robs him. Determined, Raymond tracks down the woman at a gambling club owned by Fernando while confronting several men at gunpoint to reclaim Eugene's lost money. Unbeknownst to them, Frank Grimes is quietly observing the scene from across the table.
Returning to the gambling club, Raymond and Eugene confront Grimes and pressure him for Valerie's whereabouts. Grimes confesses to his misfortune of having to frequently take Valerie to hospitals due to her excessive clumsiness, draining his finances. Eventually, he relinquished her to Fernando (portrayed by Rodrigo Puebla). Tragically, as they prepare to leave, Grimes is killed in a drive-by shooting, leaving Raymond and Eugene wrongly arrested by the police soon after.
Upon their release, they discover that Grimes had sent Valerie on a plane to Mexico City, which never landed, leading them to assume she has perished in a crash. Desperate for any sign, they charter a plane to locate the wreckage, hoping against hope that she might still be alive. During their flight, however, Eugene suffers an allergic reaction to a bee sting, causing him to swell uncontrollably. In a local field hospital, he learns from a villager about a mysterious woman who had accidentally burned down a village in her gratitude for being sheltered. Intrigued, Raymond shows the man a picture of Valerie, who immediately screams in fear.
Determined to uncover the truth, Raymond and Eugene set out towards the scorched village in search of Valerie. Yet, during the ride, Eugene nearly drives them off a cliff, prompting Raymond to explode in frustration. In a fit of anger, he reveals to Eugene that Monosoff believed that their combined bad luck could somehow bend fate in their favor. Eugene attempts to confront Raymond but only ends up injuring himself further.
Raymond takes Eugene to a local hospital and asks the nurse to provide extra care. When Eugene regains consciousness, he finds himself beside a recovering Valerie, who also bears a head injury. They joyfully stroll away, hand in hand, leaving Raymond to discover the empty beds. He soon spots them at the end of a pier and excitedly calls out to Eugene, who, in a daze, recognizes Valerie and exclaims, "Valerie?" This recognition prompts Valerie to regain her memory. The film closes with the couple gliding down a river on a pier piece, headed directly towards a looming waterfall, hinting at another twist in their tumultuous journey.
