Slaughterhouse Five opens with a chapter written from the perspective of the author, Kurt Vonnegut, describing the long process of writing a book about the bombing of Dresden, Germany in World War II, which he experienced firsthand as an American prisoner of war.

     Vonnegut describes visiting Bernard V. O'Hare, a friend from the war, in order to help him remember about Dresden. When they get together, neither man can seem to remember anything other than random, seemingly unimportant anecdotes. Bernard's wife, Mary, is initially angry with Vonnegut, as she feels books and movies tend to glorify war; the soldiers are hardly more than children, yet they are played by men like Frank Sinatra and John Wayne. Vonnegut assures her that his book will have no parts for for Sinatra or Wayne, and vows to call it "The Children's Crusade".

     Vonnegut then recounts reading about the historical Children's Crusade of 1213, in which armies of children were raised in Germany and France and sold in North Africa as slaves. He also recalls the introduction of a book about Dresden published in 1908, and describes the devastation of the city during a 1760 siege by the Prussians. Vonnegut also briefly describes going back to Dresden with O'Hare, where they made friends with Gerhard Müller, a cab driver and prisoner of the American's during WWII, who takes them to the slaughterhouse where they were imprisoned at night as POWs. Müller's mother was killed in the Dresden bombings.

     This chapter also mentions some aspects of Vonnegut's life after the war, including studying anthropology at the University of Chicago, working as a police reporter, and in a public relations job for General Electric. During this time, Vonnegut wrote to the Air Force asking for details about the raid on Dresden, but was told the information was still considered top secret.

     Chapter two begins with the novel's main action, centred around protagonist Billy Pilgrim, who says he has come unstuck in time, randomly experiencing events from different parts of his life. We are given a brief overview of Billy's life. Born in 1922, Billy is an only child who did well in school, and began attending optometry school before being drafted in the Second World War, where Billy fought in Europe, and was eventually captured by Germans. During his time at war, Billy's father is killed in a hunting accident.

     After his discharge from the army, Billy returns to optometry school, becoming engaged to the daughter of the school's founder during his senior year, and subsequently suffering a nervous breakdown. Billy is treated in a veteran's hospital, then marries his fiancee, and becomes rich from his optometry business. Billy and his wife have two children, Barbara, who goes on to marry another optometrist, and Robert, who becomes a Green Beret who fights in Vietnam. In 1968, Billy is the sole survivor of a plane crash, and during his recuperation from this ordeal, his wife dies from accidental carbon monoxide poisoning.

     After this crash, Billy goes on a late night talk radio program and discusses his experiences being kidnapped by aliens and taken to Tralfamadore, where he is displayed in a zoo. Billy also writes letters to his local newspaper describing the aliens from Tralfamadore, who are green, with hand-shaped heads, and can see in four dimensions, meaning that they see moments in time as existing simultaneously.

     Billy is writing one such letter to the newspaper in his basement, when his daughter Barbara comes over expressing concern for his mental health, believing that his recent confessions about Tralfamadore are a result of head injuries sustained in the plane crash. Billy says that he first came unstuck in time in 1944, before his encounter with the Tralfamadorians. As a chaplain's assistant in the army, Billy was called overseas to replace a chaplain's assistant who was killed in action. Arriving during the middle of the Battle of the Bulge, Billy is one of few survivors, and tags along with three other wandering soldiers, who are without food or maps. Having never been issued a helmet, overcoat, weapon, or combat boots, Billy is woefully unprepared. One of the men Billy is travelling with is Roland Weary, an eighteen-year-old from Pittsburgh who is obsessed with torture devices. Roland denigrates Billy for having been to college, and being useless at avoiding enemy fire.

     While travelling with Roland and the two scouts, Billy has his first experience transitioning through time, passing through his death, then his birth, before settling on a moment from childhood, where his father attempts to teach him to swim by throwing him in the deep end of a pool. Billy then flashes through various moments in time: visiting his mother in a care home in 1965, attending a banquet for his son's Little League team in 1958, and a drunken New Year's Eve tryst in 1961, where he passes out in the back of his car.

     Upon waking, Billy finds himself back in WWII being shaken awake by Roland Weary, who brings him back to the two experienced scouts they have been travelling with. While Billy is hallucinating from cold and exhaustion, the scouts tell Roland and Billy to find someone to surrender to, and leave them in a creek bed. Blaming Billy for his being left behind, Roland begins attacking Billy, and just before Roland can deliver a kick to Billy's exposed back, they are discovered by a group of German soldiers.