Lloyd Christmas and Harry Dunne, two kind but dimwitted young men, are best friends and roommates living in Providence, Rhode Island. Lloyd, a chip-toothed limousine driver, immediately falls in love when he meets Mary Swanson, a woman he is driving to the airport. Upon arriving and saying goodbye to Lloyd, she leaves a briefcase in the terminal. Lloyd sees this and attempts to return it to her, unaware that it contains ransom money for her kidnapped husband, Bobby, and that she intentionally left it for her husband's captors, Joe "Mental" Mentalino and J. P. Shay. Her Aspen-bound plane has already departed, leading to Lloyd running through and falling out of the jetway.
Fired from his job for leaving the scene of an accident, Lloyd returns to his apartment and learns that Harry has also been fired from his dog-grooming job after delivering dogs late to a show and accidentally getting them dirty. Mental and Shay follow Lloyd home from the airport in pursuit of the briefcase. Mistaking the crooks for debt collectors, the two flee the apartment and return later to find that Mental and Shay have ransacked the apartment and decapitated Harry's parakeet. Lloyd suggests they head to Aspen to find Mary and return the briefcase under the pretext of escaping their lonely dreary lives in Providence. At first, Harry opposes the idea, but he eventually agrees and they leave the next day.
Mental and Shay catch up to the duo at a motel that night. Posing as a hitchhiker, Mental is picked up by Harry and Lloyd while Shay secretly follows them. During a lunch stop, the duo pranks Mental with chili peppers in his burger, unaware that he has a stomach ulcer. When Mental reacts adversely, they accidentally kill him with rat poison pills (which he planned to use on them) after mistaking it for his medication. In response, police wait to intercept the two on the road to Colorado, but a distracted Lloyd takes a wrong turn and ends up driving all night through Nebraska. Upon waking up and realizing Lloyd's mishap, Harry gives up on the journey and decides to walk home, but Lloyd later persuades him to continue after trading the van for a minibike.
The two arrive in Aspen but cannot find Mary. With no money and nowhere to stay, Harry attacks Lloyd in frustration that night, breaking the briefcase open by accident; after discovering the money, the two spend it on a luxury hotel suite, clothes, and a car. They learn that Mary and her family are hosting a gala and prepare to attend. At the gala, Harry, attempting to lure Mary over to Lloyd, reluctantly agrees to go skiing with her the next day and lies to Lloyd that he got him a date. The next day, after waiting all day for Mary at the hotel bar, Lloyd finds out Harry lied and spent the day with her himself.
In retaliation, Lloyd pranks Harry by serving him a coffee laced with a potent dose of laxative, causing Harry to spontaneously defecate in a broken toilet at Mary's house. Lloyd arrives at Mary's house and informs her that he has her briefcase. He takes her to the hotel, shows her the briefcase, and confesses his love to her, but she rejects him as she is already married. Nicholas Andre, an old friend of the Swansons and the mastermind behind Bobby's kidnapping, arrives with Shay and learns that Harry and Lloyd had spent all of the ransom money and replaced it with IOUs; furious, he takes Lloyd and Mary hostage, as well as Harry when he returns. An argument leads Nicholas to shoot Harry, who plays dead before ineptly returning fire. Before Nicholas can fire another shot, an FBI team led by Beth Jordan (whom Harry had met at a gas station and Lloyd met earlier at the bar) raids the suite, where Beth tells Harry and Lloyd that the FBI and police had been following them since they left Providence. Harry reveals they gave him a bulletproof vest and gun when he arrived. Nicolas and Shay are arrested, and Mary and Bobby are reunited, much to Lloyd's dejection.
The next day, Harry and Lloyd have begun walking home on foot because all of their purchases were confiscated and their minibike has broken down. The two unintentionally decline the chance to be oil boys for a group of bikini girls, after which Harry tells Lloyd that they will get their "break" one day, then play a friendly game of tag as they walk back to Rhode Island.
Jim Carrey as Lloyd Christmas
Jeff Daniels as Harry Dunne
Lauren Holly as Mary Swanson
Karen Duffy as J.P. Shay
Mike Starr as Joe Mentalino
Charles Rocket as Nicholas Andre
Teri Garr as Helen Swanson
Victoria Rowell as Beth Jordan (credited as "Athletic Beauty")
Cam Neely as Sea Bass
Joe Baker as Barnard
Harland Williams as the motorcycle police officer
Brad Lockerman as Bobby Swanson
Lin Shaye as Mrs. Margie Neugeboren (referred to by Harry as "Mrs. Noogieburger")
Hank Brandt as Karl Swanson
Felton Perry as Detective Dale
Brady Bluhm as Billy
Connie Sawyer as elderly lady
spawned an animated TV series, a 2003 prequel, and a 2014 sequel.