Mr. Bean is a well-meaning yet clumsy and destructive security guard working at the "Royal National Gallery" in London. When the gallery's board of directors, who despise Bean for sleeping on the job, fail to fire him due to the chairman threatening repercussions, the board immediately decides on a different course of action and has him represent them during the transfer of the portrait Whistler's Mother to the Grierson Art Gallery in Los Angeles, following its purchase by philanthropist General Newton for $50 million. The curator of the Grierson, David Langley, who is impressed with the false profile of "Dr. Bean", agrees to accommodate him at his house for two months, much to the chagrin of his wife Alison, his son Kevin and daughter Jennifer. After Bean encounters mishaps with the airport police and accidentally breaks a family heirloom, Alison leaves for her mother's house along with Kevin and Jennifer.

David begins to question Bean's intelligence after he suggests they head to an amusement park where he rigs the control panel of a simulator ride to make it more exciting for him, resulting in him getting himself arrested a second time, and he later messes up a dinner with the gallery's owner George Grierson. When David questions Bean, he finds out that Bean is not a doctor after all. Bean admits to knowing absolutely nothing about art, and things get worse when he accidentally defaces the painting shortly after it arrives, by wiping it with an ink-stained handkerchief after sneezing on it and attempting to remove the stain with strong chemicals, which leave a large white patch where Bean had attempted to wipe away the mess he made. He tries to recreate the face using a pen, but fails.

Fearing that he will lose his job and possibly face criminal charges for the damage, David becomes despondent and gets drunk, even though his family returns out of pity. To save David's career and not get arrested again, Bean sneaks back into the gallery, distracts the guard by lacing his cup of coffee with laxatives and replaces the defaced painting with a modified poster. The plan works on the next day, fooling everyone including Newton. Bean nearly panics when he has to make a speech, but gives an improvised, sentimental and deep monologue about the painting that wins the crowd's praise and approval. Bean is then approached by Lieutenant Brutus (with whom he crossed paths on two earlier incidents), making David worried that he knows the truth about the priceless painting's mishap, only to learn from him that Jennifer was rushed to a hospital after being involved in a motorcycle accident along with her boyfriend, Stingo.