Lloyd Christmas is a rather inept and simple-minded limousine driver in Providence, Rhode Island, who becomes infatuated with his passenger, Mary Swanson, as he drives her to the airport. Mary is heading home to her family in Aspen, Colorado. She drops off a briefcase with a large sum of cash at the airport terminal, as ransom money for her kidnapped husband, unbeknown to Lloyd. Lloyd witnesses the drop-off, and, thinking Mary has left the briefcase by mistake, intercepts the package before the kidnapper's accomplices pick up their pay, dashing ahead of them to snag the briefcase. Lloyd is unable to catch Mary in time, and is left on the tarmac of the airport with briefcase in hand
Harry Dunne, Lloyd's roommate, is in the pet grooming business, and has recently spent his life savings converting his van (a 1984 Ford Econoline) into a sheepdog. Both Lloyd and Harry quickly lose their jobs due to preventable accidents, and the two are distraught over their situation. Thinking Lloyd is a "professional" hired by the Swansons, or perhaps an FBI agent, the kidnappers exact revenge on Harry and Lloyd by beheading Harry's pet parakeet while the pair are out looking for new jobs. Lloyd convinces Harry they should leave their messed up lives in Providence behind and head for Aspen to return the briefcase to Mary, unaware the locked briefcase contains enough money to support them both.
On their way to Aspen, Harry and Lloyd have several misadventures, they inadvertently kill one of the kidnappers by accidentally feeding him rat poison, and wind up separating when Lloyd takes a wrong turn and drives them to Nebraska instead of Colorado. Out of gas and infuriated by Lloyd's mistake, Harry begins walking home, but Lloyd is able to trade the van for a small scooter, he catches up with Harry and the two proceed to Aspen.
Eventually the two are found out by the man behind the kidnapping plot, Nicolas Andre, a long time confidant of the Swanson family, who holds the three in their hotel room at gunpoint. When Lloyd reveals all the money is gone, replaced with I.O.U.'s written on dirty napkins, the kidnapper freaks and almost kills the pair. The FBI intercept, and Mary is reunited with her husband, much to Lloyd's dismay, who didn't even realize Mary was married.