After the publication of his fourth and most successful novel, Kennedy Fathers (based on Katie), Danny stops teaching and focuses on writing.

Danny, who has now lost his mother, father, son and their friend, tries to focus on writing his next book, a follow-up to his previous eight semi-autobiographical novels.

[11] To make the novel as authentic as possible, Irving used a cousin in the logging business to help locate "an old-time log-driver alive, alert and literate enough in English to read [his] manuscript" (many loggers in New Hampshire were French-speaking Québécois).

[16] Last Night in Twisted River was included in Time magazine's 2009 list of "the fall's most anticipated movies, books, TV shows, albums and exhibits".

[2] Last Night in Twisted River is John Irving's 12th novel and his "most ambitious",[17] spanning five decades from 1954 to 2005 and taking place mostly in the northeastern United States and southern Ontario in Canada.

[18] It is about the relationship between three men:[19] Dominic Baciagalupo, an Italian-American cook with "the look of a man long resigned to his fate",[20] his son Daniel (Danny), who grows up to be a famous novelist, and Ketchum, a "foul-mouthed logger with a heart of gold".

[9] Irving modelled Danny's career loosely on his own: both are the same age; both get a scholarship to Phillips Exeter Academy; both are taught by Kurt Vonnegut at the University of Iowa and go on to become famous novelists;[23] both are "Kennedy fathers" enabling them to claim paternity deferment during the Vietnam war;[a][25] both have their first success with their fourth novel (Kennedy Fathers and The World According to Garp).

[19] Danny and Irving's sixth books, East of Bangor and The Cider House Rules are both abortion novels set in a Maine orphanage which both later win an Oscar for Best Adapted Screenplay.

[22] In The Times Helen Rumbelow said Irving "almost rivals Paul Auster for the mischievous way he inserts a thinly fictionalized version of himself into the tale".

[26] Many themes present in Irving's earlier works are recycled in this book: the story begins in New England, it features a fractured family, a main character is a writer, sudden tragedy, a young boy is sexually initiated by an older woman and bears.

[18] Daniel Mallory in the Los Angeles Times said that while Irving "loots his own canon", so do other writers, for example Philip Roth, Richard Ford and Don DeLillo.

[27] Lucy Daniel wrote in The Daily Telegraph that while such "predictable eccentricities" might disadvantage a writer, they are "part of the charm" of Irving's works.

[17] The narrative moves back and forth in time, with each new section leaping forward 10 to 30 years, and then backtracking, in "fits and starts"[28] to fill in the missing details.

[28] Rodriguez said these "sudden shifts in points of view that give new meaning to the passage you have just read and leaps in chronology that keep crucial incidents offstage" makes it an "agile, sometimes tricky novel", and the closest Irving has come to writing metafiction.

[29] Lucy Daniel in The Daily Telegraph called the book "Moralistic, perverse, funny and uplifting", but added that it was debatable if it was "clever metafiction", or a "thinly disguised memoir".

English author Giles Foden wrote in The Guardian that Ketchum is "[a] magnificent creation, he's like something out of The Last of the Mohicans",[31] while Ron Charles said in The Washington Post that he is "one of Irving's most endearing and memorable characters", a cross between Shakespeare's Falstaff and Louise Erdrich's Nanapush.

[20] Literary critic Michiko Kakutani in The New York Times described Constable Carl, the policeman who pursues Dominic and Danny, as not unlike Victor Hugo’s obsessive Inspector Javert in Les Misérables.

[3] Kakutani was also critical of the novel, saying that with some "diligent editing" it could have equaled some of Irving's more powerful works, in particular The World According to Garp (1978) and A Widow for One Year (1998).

[18] She said while it was at times a "deeply felt and often moving story", it was tarnished by a "gimmicky plot; cartoony characters; absurd contrivances; cheesy sentimentality; and a thoroughly preposterous ending".

[18] English novelist and critic Stephanie Merritt wrote in The Observer that once Carl finds Dominic and Danny, the novel "loses momentum and becomes more didactic", and that the "sheer exuberance of detail ... at times threatens to overwhelm the story".

[9] Joanna Scott wrote in The New York Times that she liked the sensory sensations Irving evoked in the book, in particular those brought on by Dominic's cooking.

She also found some of the book's comical scenes, including the naked female skydiver landing in a pigpen, "among the most memorable that Irving has written".

He found the flight of the father and son a "brilliant plot device", and was fascinated by the details of the restaurant business and the process of writing novels.

[21] He said he performs "the most death-defying of literary feats: negotiat[ing] the delicate line between familiarity and novelty in such impressive style as to create a work that is at once comfortable, vintage Irving yet wholly new and unique".

[20] Charles was particularly critical of the fact that the book dwelt excessively on Danny's writing career, which mirrored Irving's, saying that it was "shorthand for real storytelling, for creating colorful places full of well-developed characters".

[20] William Kowalski in The Globe and Mail questioned why the book was not released as a memoir as there are times when Irving appears to have modeled Danny "literally after himself".

[19] For Rene Rodriguez in the Los Angeles Times, the highlight of the book was the attention it gave to the bond between Dominic and his son, but she did feel that the details of the creative process should have been relegated to an essay.