A log driving accident on the Twister River in the small logging settlement sets the plot of the novel in the northern New Hampshire. In a story spanning five decades, Last Night in Twisted River depicts the recent half-century in the United States as "a living replica of Coos County, where lethal hatreds were generally permitted to run their course.
A young logger, Angel, who slipped and fell under the logs dies. Dominic Baciagalupo is the camp's Italian-American cook who lives above the kitchen with his 12-year old son, Daniel. "Injun Jane", the kitchen's dishwasher and girlfriend of the local law officer, Constable Carl, is having an affair with Dominic.
One night, mistaking her for a bear attacking his father, Daniel kills her with an eight-inch cast-iron skillet.
Dominic takes Jane's body and deposits it on the kitchen floor of Carl's house, knowing that Carl will be passed out drunk and will probably believe he killed her, as he often beat her up. Early the next morning Dominic and Daniel tell Ketchum what happened and flee Twisted River in case the bad-tempered Carl finds out what really happened.
Ketchum keeps in touch with both Dominic and Danny via telephone and letters, and warns them that Carl is looking for them. Ketchum tells Dominic to join Danny in Vermont. He changes his name to Tony Angel, father of the writer Danny Angel.
While Danny teaches writing at Windham College, Tony opens and runs his own restaurant. After the publication of his fourth and most successful novel, Kennedy Fathers Danny stops teaching and focuses on writing.
Then in 1983, two of the saw mill's wives in Twisted River are passing through Vermont and stop for a meal at Tony's restaurant. They recognize Tony and later tell Carl where "Cookie" is. Again, on Ketchum's advice, the father and son are forced to flee, this time to Toronto.
With their cover blown, Tony and Danny revert back to their original names.
Then in 2001, Ketchum gets careless and unwittingly leads Carl to Dominic and Danny's house in Toronto.
Carl shoots and kills Dominic and Danny retaliates by shooting and killing Carl. Ketchum is devastated at having failed to protect his friends and takes his own life at Twisted River.
The heart of the story comes not from the big events but from the characters. Excepting the accidental homicide that comes to haunt them, they lead ordinary lives. They meet and leave lovers, start families, get dogs, change jobs.