Daniel Hillard is a talented but irresponsible voice actor in San Francisco, who loves his three children deeply. After a tumultuous birthday party for his son Chris, which leads to an argument with his wife Miranda, she files for divorce. Daniel's unconventional parenting style conflicts with Miranda's desire for structure, resulting in a custody ruling that favors Miranda, leaving Daniel devastated. With limited visitation rights and struggling to find a stable job, Daniel becomes desperate to spend more time with his children.

In an attempt to see his children more, Daniel hatches a plan when Miranda places an ad for a housekeeper. With the help of his brother Frank, a makeup artist, Daniel transforms into Mrs. Doubtfire, a kind, elderly British woman, and successfully applies for the job. As Mrs. Doubtfire, Daniel is able to be close to his children, learning more about their lives and beginning to understand the complexities of parenting and his mistakes. This new role offers him a unique perspective on his family's dynamics and his relationship with his children, while at the same time, Miranda starts to appreciate the positive changes in her household, not knowing the real identity of her new housekeeper.