Two good-hearted but incredibly dimwitted friends, Lloyd Christmas and Harry Dunne, stumble across a suitcase left behind in Lloyd's limousine by a woman named Mary at the airport. Believing it was an accident, Lloyd is smitten by Mary and convinces Harry that they must return the suitcase to her. They set out on a cross-country road trip from Providence, Rhode Island to Aspen, Colorado, unaware that the suitcase is actually connected to a kidnapping and contains ransom money. Their journey is marked by a series of comedic misadventures and misunderstandings, highlighting their lack of intellect and awareness.

Throughout their trip, Lloyd and Harry unintentionally thwart the plans of the kidnappers attempting to retrieve the suitcase, all the while believing they are on a noble mission to help Mary. Their unwavering naiveté and optimism lead them into various ridiculous situations, from inadvertently killing a rare bird to embroiling themselves in law enforcement mishaps. Despite the chaos they leave in their wake, their friendship and determination to do what they believe is right keeps them oblivious to the danger and complexity of the situation surrounding the suitcase.