Larry Wilson (Andrew McCarthy) and Richard Parker (Jonathan Silverman) are two low-level financial employees at an insurance corporation in New York City. While going over actuarial reports, Richard discovers a series of payments made for the same death. Richard and Larry take their findings to the CEO, Bernie Lomax (Terry Kiser), who commends them for discovering insurance fraud and invites them to his Hamptons island beach house for the Labor Day weekend. Unbeknownst to Larry and Richard, Bernie is behind the fraud. Nervously meeting with his mob partner Vito (Louis Giambalvo), Bernie asks to have Larry and Richard killed. However, after Bernie leaves, Vito decides Bernie has been attracting too much attention with his greed and his relationship with Vito's girlfriend, Tina (Catherine Parks), and orders that he be killed instead.
Bernie arrives at the island before Larry and Richard and plans the murders with Paulie (Don Calfa), the hitman, on the phone, unaware the conversation is being recorded on his answering machine. Bernie then plants cash and a fake confession note implicating Larry and Richard in the insurance fraud. Paulie arrives, killing Bernie with a drug overdose. When Larry and Richard arrive at Bernie's house, they find Bernie's body. Before they can call the police, guests arrive for a party that Bernie used to host every weekend. To Larry and Richard's amazement, the guests are too engrossed in their partying to notice he is dead, with the dopey grin from the fatal injection and his sunglasses concealing his lifeless state. Fearing implication in Bernie's death, and wanting to enjoy the luxury of the house for the weekend, Larry proposes he and Richard maintain the illusion that Bernie is still alive, a notion that Richard finds absurd. Only the arrival of Richard's office crush, Gwen Saunders (Catherine Mary Stewart), a summer intern for the company, convinces him to go along with Larry's plan.
Later that night, Tina arrives at the house, and has Larry and Richard direct her to Bernie. There, she also fails to realize he is dead. At that moment, Marty, one of Vito's mobsters witnesses the two of them apparently making love. Fooled into thinking Bernie's assassination failed, he notifies Paulie. The next morning, Richard is appalled to discover Larry furthering the illusion of Bernie being alive by manipulating his body's limbs. Richard attempts to call the police but instead activates the phone message detailing Bernie's plot against them. Unaware of the circumstances of Bernie's death, they mistakenly believe they are still the targets of a mob hit and decide to use Bernie's corpse as a prop for protection. Richard and Larry make various attempts to leave the island. All attempts are thwarted, as they repeatedly misplace and recover Bernie's body. Finally, Larry and Richard are forced to return to Bernie's home. Meanwhile, Paulie, unhinged at his apparent failure to kill Bernie, returns to the island.
At the house, Gwen confronts Larry and Richard, who confess that Bernie has been dead since their arrival. Paulie then appears and opens fire at Bernie, then turns his attention to Larry, Richard, and Gwen. Chasing after the trio, Paulie corners Larry, who clumsily manages to subdue him with a phone cord and a punch. The police eventually arrive and place Paulie under arrest, taking him away in a straitjacket as he continues to insist Bernie is still alive. Bernie is loaded into an ambulance, however, his gurney rolls away and topples off the boardwalk, dumping him onto the beach right behind Richard, Larry, and Gwen, who run away after noticing him. Eventually, a young boy comes along and starts to "play" with Bernie, scooping buckets of sand over his body.
The film received mixed reviews from critics, holding a 52% rating on Rotten Tomatoes. Peter Travers of Rolling Stone called the film "tasteless" and "crude" and felt that in the end it was impossible to "drag one tired joke around for nearly two hours. Like Bernie, the movie ends up dead on its feet." Roger Ebert echoed this sentiment, arguing that movies centered on dead bodies are rarely funny. Ebert gave the film 1 out of 4 stars overall.
Nevertheless, the film was a financial success, grossing US$30 million at the box office, and was profitable on home video, as well as becoming a cult classic.
The film's commercial success inspired a 1993 sequel, Weekend at Bernie's II.
On January 24, 2014, director Ted Kotcheff and screenwriter Robert Klane filed a lawsuit against Metro-Goldwyn-Mayer and 20th Century Fox for breach of contract for profits they claimed were due from the film.