Tommy Spinelli, a seasoned wiseguy, finds himself in a rather precarious situation when he is tasked by the bumbling hitmen Benny and Rico to transport a disturbing cargo—a duffel bag brimming with severed human heads—across the country to their intimidating crime boss, Big Sep. As Tommy boards a commercial flight, his journey inadvertently collides with that of Charlie Pritchett, a spirited young American tourist who is eager to reunite with his girlfriend, Laurie, and her parents, Dick and Annette, during their trip to Mexico.
Once the flight arrives at their destination, the shadow of Tommy's sinister presence looms large. He coerces Charlie's friends, Ernie and Steve, into revealing their secrets while Charlie and Laurie desperately try to escape the looming disaster tied to the malevolent luggage they inadvertently claimed.
Upon their arrival at the sun-soaked Acapulco resort, the unsuspecting family encounters a nightmarish mix-up when they receive Tommy's own grisly bag, rather than their belongings. Annette, battling her own insecurities and the effects of alcohol, begins to suspect that Charlie could be a serial killer on the run, especially after she stumbles upon one of the severed heads while stashing a gift inside his luggage. Her husband, Dick, however, dismisses her frantic notions as the wild imagination of someone struggling with a drinking problem.
As Charlie and Laurie scramble to dispose of the heads, they unwittingly get caught in a whirlwind of chaotic adventures. A gang of roughnecks swipes their vehicle, compelling Charlie to devise a clever ruse of pretending to forget the severed heads at college. However, just when they think they’re evading calamity, Dick unwittingly takes one of the heads onto their next journey, leading to his arrest.
Meanwhile, Tommy, along with Ernie and Steve, embarks on a mission to replace the stolen cargo by targeting a cryonics lab stocked with bodies and severed heads, a prospect that fills Tommy with glee. Following his retrieval of the replacement heads, the trio boards a flight back to Mexico, with Tommy issuing a chilling warning: if Charlie loses more heads, he'll start replacing them with one of his friends or family members.
When the airport fracas finally reaches Benny and Rico's ears, they realize that they need to intervene and reclaim the heads themselves. Just as the scene grows increasingly chaotic with the arrival of Fern in Mexico, Tommy takes drastic measures by capturing Dick's mother along with the others, while Charlie becomes desperate to recover the severed heads. Things get even more tangled when they discover that a coyote has made off with one of the heads from the stolen vehicle. As Benny and Rico put the pressure on Tommy, threatening to end him if he doesn't successfully transport the heads across the border in time, Charlie hatches a daring plan to save everyone involved.
In a determined attempt to clear his father's name, Charlie and Laurie make a bold move to the airport with a severed head as evidence of innocence. Though Benny and Rico try to disrupt their efforts, their plans unravel, leading to their eventual arrest—an outcome that is ingeniously orchestrated by both Tommy and Charlie. With a grateful heart, Charlie thanks Tommy for his help before Tommy heads off to a long-awaited retirement in Hawaii.
However, the weight of chaos doesn’t simply vanish. Steve, growing increasingly erratic, wheels around the airport, proclaiming that the severed head is his "best friend," leaving security guards in a state of confusion over his bizarre antics.
In the end, as calm returns, Charlie and Laurie prepare for their next chapter—tying the knot in a joyful ceremony attended by Laurie's parents, with Steve restrained in a straitjacket adding an unexpected twist. Ernie also shines in the festivities, now donned as a brilliant brain surgeon. Meanwhile, Fern returns unexpectedly, having been ousted from a moving van, yet Tommy remains unfazed by her harsh jabs, contentedly savoring his retirement in the tranquility of paradise.
