Daniel Hillard is a freelance voice actor living in San Francisco. Though a devoted father to his three children, Lydia, Chris, and Natalie, his wife Miranda considers him unreliable. One day, Daniel quits his job after a disagreement over a questionable script and returns home to throw a chaotic birthday party for Chris, despite Miranda’s objections. This infuriates Miranda to the point where she files for divorce. At their first custody hearing, the court grants sole custody of the children to Miranda; shared custody is contingent on whether Daniel finds a steady job and a suitable residence within three months.
As Daniel works to rebuild his life, securing himself an apartment and a new job as a shipping clerk at a TV station, he learns that Miranda is seeking a housekeeper. He secretly alters her classified ad form, then calls Miranda while using his voice acting skills to pose as a series of undesirable applicants. He finally calls Miranda as "Mrs. Euphegenia Doubtfire", a British-accented nanny with strong credentials. Miranda is impressed and invites Mrs. Doubtfire for an interview. Daniel asks his brother Frank, a makeup artist, and Frank's partner, Jack, to create a Mrs. Doubtfire costume, including a prosthetic mask to make him appear as an older woman.
Miranda hires Mrs. Doubtfire after a successful interview. The children initially struggle under Mrs. Doubtfire's authority but soon come around and thrive and Miranda learns to become closer with her children. Daniel learns several household skills as part of the role, further improving himself. However, this later creates another barrier for him to see his children, as Miranda puts more trust into Mrs. Doubtfire than him and cannot bring herself to dismiss her. One night, Lydia and Chris discover that Mrs. Doubtfire is actually Daniel; thrilled to have their father back, they agree to keep his secret.
One day, the station's CEO Jonathan Lundy sees Daniel playing with toy dinosaurs on the set of a poorly-rated children's show. Impressed by his voice acting and imagination, Lundy invites Daniel for a dinner to discuss his plans for the show. Daniel discovers this is to be at the same place and time as a planned birthday dinner for Miranda by her new boyfriend Stuart Dunmeyer, to which Mrs. Doubtfire is invited. Unable to change either appointment, Daniel changes in-and-out of the Mrs. Doubtfire costume to attend both events. Becoming drunk, Daniel slips up when he accidentally returns to Lundy in his costume, but he quickly claims that Mrs. Doubtfire is his idea for the new show. After overhearing that Stu is allergic to pepper, Daniel sneaks into the kitchen and seasons Stu's order of jambalaya with powdered cayenne pepper. Stu chokes on his dinner, and Daniel, feeling guilty, administers the Heimlich maneuver as Mrs. Doubtfire. The action causes the prosthetic mask to partially peel off Daniel's face, revealing his identity and horrifying Miranda, who storms out of the restaurant with the kids.
At their next custody hearing, Daniel points out that he has met the judge's requirements, then explains his actions. The judge, while sympatheic, considers Daniel's ruse as Mrs. Doubtfire unorthodox, and grants Miranda full custody, further restricting Daniel's rights to supervised Saturday visits, which devastates him. Without Mrs. Doubtfire, Miranda and her children become miserable, acknowledging how much "she" improved their lives. They are then surprised to discover that Daniel, as Mrs. Doubtfire, is hosting a new children's show called Euphegenia's House, which becomes a nationwide hit.
Miranda visits Daniel on set after filming and admits that things were better when he was involved with the family. She then arranges joint custody, allowing Daniel as himself to take the children after school. As Daniel leaves with the kids, Miranda watches an episode of Euphegenia's House in which Mrs. Doubtfire answers a letter from a young girl whose parents have separated, saying that no matter what arrangements families have, love will prevail.
Robin Williams as Daniel Hillard / Mrs. Doubtfire
Sally Field as Miranda Hillard
Pierce Brosnan as Stu
Harvey Fierstein as Frank
Polly Holliday as Gloria
Lisa Jakub as Lydia Hillard
Matthew Lawrence as Chris Hillard
Mara Wilson as Natalie Hillard
Robert Prosky as Mr. Lundy
Anne Haney as Mrs. Sellner
Scott Capurro as Jack
Martin Mull as Justin Gregory
William Newman as Mr. Sprinkles
based on the 1987 novel Alias Madame Doubtfire by Anne Fine