The story begins with a gruesome introduction where two unsuspecting protagonists, a reporter and a cameraman, meet a tragic end. However, the narrative quickly rewinds to explore the events that lead to this disturbing conclusion. Set against the stunning backdrop of West Virginia, nine college friends—Allison, Chad, Chloe, Chuck, Jason, Naomi, Todd, Mitch, and Mike—embark on a camping trip three days earlier. Their idyllic escape takes an unforeseen turn when they cross paths with Tucker and Dale, two well-meaning hillbillies who have just acquired their dream vacation spot: a dilapidated lakefront cabin nestled in the woodland.
As they make their way toward the cabin, Tucker offers his friend Dale some wise advice, coaxing him to strike up a conversation with Allison. Unfortunately, Dale's rugged appearance and self-doubt inadvertently terrify the college group, causing them to flee in panic. Upon reaching their cabin, Tucker and Dale begin renovating their newfound hideaway. Meanwhile, in a nearby area, Chad enthralls his friends with a spine-chilling story of the "Memorial Day Massacre," a horrific attack by hillbillies that occurred two decades ago.
As night descends and the college group ventures deeper into the woods for an impromptu skinny-dipping adventure, they unwittingly stumble upon Tucker and Dale engaged in a peaceful fishing outing. When Allison accidentally takes a plunge, Tucker and Dale rush in heroically to save her from drowning. However, her friends mistakenly interpret their gestures as an attempted abduction, setting off a hilarious chain of misunderstandings.
The following morning, Allison wakes up in Tucker and Dale's cabin, initially filled with fear but gradually warmed by the duo’s friendly demeanor. Meanwhile, her friends arrive with the intention of rescuing her from what they believe are her "psychopathic captors." Chuck, being the rational one, decides to call the authorities, while Dale and Allison's bond grows stronger inside the cabin.
Disaster strikes when Tucker, in an unfortunate mishap, disrupts a beehive, inciting the hornets into a furious frenzy. In a state of panic, he waves around a chainsaw, leading the college group to interpret this as an act of aggression. The chaos that ensues results in Mitch tragically impaling himself on a broken tree branch, further fueling Chad's paranoia as he convinces himself and the others that they must fight for survival.
As Allison’s friends rush to the cabin, they witness a shocking scene: she is working alongside Tucker and Dale to build an outhouse, which unsettlingly resembles a coffin. Their misinterpretation leads to a comedic assault, resulting in Todd accidentally impaling himself while trying to attack Dale, and Mike meeting a grisly fate in a wood chipper. Meanwhile, Allison is knocked unconscious by Dale’s unwitting actions, leading him to carry her inside for safety. The college kids' growing belief that Tucker and Dale have killed their friends only intensifies their hysteria.
Amidst the spiraling confusion, Chuck returns with Sheriff Gurr, who expresses doubt regarding the notion that they are dealing with deranged hillbillies. However, Gurr meets a tragic end after a loose beam crashes down on him, setting in motion a series of darkly comedic events. Chuck's attempt to threaten Tucker and Dale with his firearm inadvertently leads to yet another accidental death, leaving only Chad alive.
Eager for revenge against those he thinks have wronged him, Chad returns, determined to capture Tucker. But when he finds himself tied upside down to a tree by Dale’s quick thinking, he begins to torment Tucker, leading to a brutal encounter where he loses two fingers as a grim warning to Dale. This only escalates the absurdity of their misunderstandings and enlarges the tension building among the characters.
As the chaos reaches its peak, Tucker bravely ventures out to rescue his friend while Chad and Naomi navigate their moral choices amidst the turmoil. Allison, now free from her so-called captivity, strives to bridge the gap of misunderstanding with Chad and Naomi, but is met with their continued mistrust. The fragile agreement among them is short-lived when Tucker and Dale return, bringing a new wave of insanity that ends catastrophically for Naomi, Chloe, and Jason.
In the aftermath, a crazed and disfigured Chad becomes obsessed with vengeance, driven by a twisted desire for retribution. While Tucker and Dale regroup and strategize, they uncover that Chad’s relentless pursuit of revenge is rooted in a deep need to avenge his father, one of the notorious hillbillies involved in the Memorial Day Massacre two decades ago.
As the truth slowly unveils itself, Dale confronts the deranged Chad, who is fixated on wreaking havoc. Not to be outdone, Dale cleverly concocts a plan involving chamomile tea to trigger an asthma attack in Chad, leading to his dramatic fall from an upstairs window.
In the wake of the mayhem, the media descends upon the scene, casting a shadow of doubt on the tragic events that have transpired. As Tucker recovers in the hospital, he faces the grim realities of their situation while watching the news report. Meanwhile, Dale visits him with good news: he has successfully asked Allison out on a date, hoping to enjoy a romantic evening of bowling.
As night falls, Dale imparts wisdom to Tucker, encouraging him in his quest for love to "just be himself." In a touching scene, as the two heroes share a kiss at the bowling alley, a new misunderstanding looms on the horizon, setting the stage for yet more chaos to unfold in their unsuspecting community.
