Harold Crick (WILL FERRELL) is an unassuming auditor for the IRS whose life is all about numbers, be that in his line of work, or how many strokes he uses to brush his teeth, steps are to the bus stop, and such. We know this because we hear a narrator (EMMA THOMPSON) describing his lifestyle. Suddenly one day, he can hear her too, an unnerving aural discovery that no one else -- such as his coworker Dave (TONY HALE) -- can hear, eventually leading Harold to a psychiatrist who assumes he's suffering from schizophrenia.
When he doesn't accept that since the voice has a better vocabulary than he does, he's sent to meet literary professor Dr. Jules Hilbert (DUSTIN HOFFMAN) who initially doesn't believe him. Yet, when Harold states that his mystery narrator uses the term "little did he know," Jules becomes intrigued and decides to try to decipher what writer is in his head.
Little does either initially know that it's Kay Eiffel (EMMA THOMPSON), a fairly famous author with a penchant for killing off her protagonists in her works. Since writer's block has her stymied regarding the latest such literary act, her publisher has sent writing assistant Penny Escher (QUEEN LATIFAH) to see if she can help. Of course, since Harold turns out to be the physical manifestation of Kay's latest novel, that means his life is literally in their hands.
All of which is too bad since he's finally started to come out of his shell, mostly after having become smitten with bohemian bakery shop owner Ana Pascal (MAGGIE GYLLENHAAL) who he's auditing for failure to pay her taxes. As their initially antagonistic relationship blossoms into something else, it's a race against time for Harold and Jules to figure out the narrator's identity before she kills off Harold in her book and thus, presumably, in real life.