The financial security and social prosperity that the Vonneguts once enjoyed were destroyed in a matter of years. The Liebers's brewery was closed in 1921 after the advent of Prohibition in the United States. When the Great Depression hit, few people could afford to build, causing clients at Kurt Sr.'s architectural firm to become scarce. Vonnegut's brother and sister had finished their primary and secondary educations in private schools, but Vonnegut was placed in a public school, called Public School No. 43, now known as the James Whitcomb Riley School. He was not bothered by this, but both his parents were affected deeply by their economic misfortune. His father withdrew from normal life and became what Vonnegut called a "dreamy artist". His mother became depressed, withdrawn, bitter, and abusive. She labored to regain the family's wealth and status, and Vonnegut said she expressed hatred "as corrosive as hydrochloric acid" for her husband. Edith Vonnegut forayed into writing and tried to sell short stories to magazines like Collier's and The Saturday Evening Post with no success.

Kurt Vonnegut Jr. was born on November 11, 1922 in Indianapolis, Indiana. He was the youngest of three children of Kurt Vonnegut Sr. and his wife Edith (née Lieber). His older siblings were Bernard (born 1914) and Alice (born 1917). Vonnegut was descended from German immigrants who settled in the United States in the mid-19th century; his patrilineal great-grandfather, Clemens Vonnegut of Westphalia, Germany, settled in Indianapolis and founded the Vonnegut Hardware Company. Kurt's father, and his father before him, Bernard, were architects; the architecture firm under Kurt Sr. designed such buildings as Das Deutsche Haus (now called "The Athenæum"), the Indiana headquarters of the Bell Telephone Company, and the Fletcher Trust Building. Vonnegut's mother was born into Indianapolis high society, as her family, the Liebers, were among the wealthiest in the city, their fortune derived from ownership of a successful brewery.

Vonnegut enrolled at Shortridge High School in Indianapolis in 1936. While there, he played clarinet in the school band and became a co-editor (along with Madelyn Pugh) for the Tuesday edition of the school newspaper, The Shortridge Echo. Vonnegut said his tenure with the Echo allowed him to write for a large audience—his fellow students—rather than for a Teacher, an experience he said was "fun and easy". "It just turned out that I could write better than a lot of other people", Vonnegut observed. "Each person has something he can do easily and can't imagine why everybody else has so much trouble doing it."

After graduating from Shortridge in 1940, Vonnegut enrolled at Cornell University in Ithaca, New York. He wanted to study the humanities or become an Architect like his father, but his father and brother, a scientist, urged him to study a "useful" discipline. As a result, Vonnegut majored in biochemistry, but he had little proficiency in the area and was indifferent towards his studies. As his father had been a member at MIT, Vonnegut was entitled to join the Delta Upsilon fraternity, and did. He overcame stiff competition for a place at the university's independent newspaper, The Cornell Daily Sun, first serving as a staff Writer, then as an Editor. By the end of his freshman year, he was writing a column titled "Innocents Abroad" which reused jokes from other publications. He later penned a piece, "Well All Right", focusing on pacifism, a cause he strongly supported, arguing against U.S. intervention in World War II.

Born and raised in Indianapolis, Indiana, Vonnegut attended Cornell University but dropped out in January 1943 and enlisted in the United States Army. As part of his training, he studied mechanical engineering at Carnegie Institute of Technology (now Carnegie Mellon University) and the University of Tennessee. He was then deployed to Europe to fight in World War II and was captured by the Germans during the Battle of the Bulge. He was interned in Dresden and survived the Allied bombing of the city by taking refuge in a meat locker of the slaughterhouse where he was imprisoned. After the war, Vonnegut married Jane Marie Cox, with whom he had three children. He later adopted his sister's three sons, after she died of cancer and her husband was killed in a train accident.

Three months after his mother's suicide, Vonnegut was sent to Europe as an intelligence scout with the 106th Infantry Division. In December 1944, he fought in the Battle of the Bulge, the final German offensive of the war. During the battle, the 106th Infantry Division, which had only recently reached the front and was assigned to a "quiet" sector due to its inexperience, was overrun by advancing German armored forces. Over 500 members of the division were killed and over 6,000 were captured.

After he returned to the United States, 22-year-old Vonnegut married Jane Marie Cox, his high school girlfriend and classmate since kindergarten, on September 1, 1945. The pair relocated to Chicago; there, Vonnegut enrolled in the University of Chicago on the G.I. Bill, as an anthropology student in an unusual five-year joint undergraduate/graduate program that conferred a master's degree. He augmented his income by working as a reporter for the City News Bureau of Chicago at night. Jane accepted a scholarship from the university to study Russian literature as a graduate student. Jane dropped out of the program after becoming pregnant with the couple's first child, Mark (born May 1947), while Kurt also left the University without any degree (despite having completed his undergraduate education) when his master's thesis on the Ghost Dance religious movement was unanimously rejected by the department.

Shortly thereafter, General Electric (GE) hired Vonnegut as a publicist for the company's Schenectady, New York, research laboratory. Although the job required a college degree, Vonnegut was hired after claiming to hold a master's degree in anthropology from the University of Chicago. His brother Bernard had worked at GE since 1945, contributing significantly to an iodine-based cloud seeding project. In 1949, Kurt and Jane had a daughter named Edith. Still working for GE, Vonnegut had his first piece, titled "Report on the Barnhouse Effect", published in the February 11, 1950 issue of Collier's, for which he received $750. Vonnegut wrote another story, after being coached by the fiction Editor at Collier's, Knox Burger, and again sold it to the magazine, this time for $950. Burger suggested he quit GE, a course he had contemplated before. Vonnegut moved with his family to Cape Cod, Massachusetts to write full-time, and left GE in 1951.

Vonnegut called George Orwell his favorite Writer, and admitted that he tried to emulate Orwell. "I like his concern for the poor, I like his socialism, I like his simplicity", Vonnegut said. Vonnegut also said that Orwell's Nineteen Eighty-Four, and Brave New World by Aldous Huxley, heavily influenced his debut novel, Player Piano, in 1952. Vonnegut commented that Robert Louis Stevenson's stories were emblems of thoughtfully put together works that he tried to mimic in his own compositions. Vonnegut also hailed Playwright and socialist George Bernard Shaw as "a hero of [his]", and an "enormous influence." Within his own family, Vonnegut stated that his mother, Edith, had the greatest influence on him. "[My] mother thought she might make a new fortune by writing for the slick magazines. She took short-story courses at night. She studied magazines the way gamblers study racing forms."

After Player Piano, Vonnegut continued to sell short stories to various magazines. In 1954 the couple had a third child, Nanette. With a growing family and no financially successful novels yet, Vonnegut's short stories sustained the family. In 1958, his sister, Alice, died of cancer two days after her husband, James Carmalt Adams, was killed in a train accident. Vonnegut adopted Alice's three young sons—James, Steven, and Kurt, aged 14, 11, and 9 respectively.

Grappling with family challenges, Vonnegut continued to write, publishing novels vastly dissimilar in terms of plot. The Sirens of Titan (1959) features a Martian invasion of Earth, as experienced by a bored Billionaire, Malachi Constant. He meets Winston Rumfoord, an aristocratic space traveler, who is virtually omniscient but stuck in a time warp that allows him to appear on Earth every 59 days. The Billionaire learns that his actions and the events of all of history are determined by a race of robotic aliens from the planet Tralfamadore, who need a replacement part that can only be produced by an advanced civilization in order to repair their spaceship and return home—human history has been manipulated to produce it. Some human structures, such as the Kremlin, are coded signals from the aliens to their ship as to how long it may expect to wait for the repair to take place. Reviewers were uncertain what to think of the book, with one comparing it to Offenbach's opera The Tales of Hoffmann.

Also published in 1961 was Vonnegut's short story, "Harrison Bergeron", set in a dystopic Future where all are equal, even if that means disfiguring beautiful people and forcing the strong or intelligent to wear devices that negate their advantages. Fourteen-year-old Harrison is a genius and athlete forced to wear record-level "handicaps" and imprisoned for attempting to overthrow the government. He escapes to a television studio, tears away his handicaps, and frees a ballerina from her lead weights. As they dance, they are killed by the Handicapper General, Diana Moon Glampers. Vonnegut, in a later letter, suggested that "Harrison Bergeron" might have sprung from his envy and self-pity as a high school misfit. In his 1976 biography of Vonnegut, Stanley Schatt suggested that the short story shows "in any leveling process, what really is lost, according to Vonnegut, is beauty, grace, and wisdom". Darryl Hattenhauer, in his 1998 journal article on "Harrison Bergeron", theorized that the story was a satire on American Cold War misunderstandings of communism and socialism.

With Cat's Cradle (1963), Allen wrote, "Vonnegut hit full stride for the first time". The narrator, John, intends to write of Dr. Felix Hoenikker, one of the fictional fathers of the atomic bomb, seeking to cover the scientist's human side. Hoenikker, in addition to the bomb, has developed another threat to mankind, ice-9, solid water stable at room temperature, and if a particle of it is dropped in water, all of it becomes ice-9. Much of the second half of the book is spent on the fictional Caribbean island of San Lorenzo, where John explores a religion called Bokononism, whose holy books (excerpts from which are quoted), give the novel the moral core science does not supply. After the oceans are converted to ice-9, wiping out most of humankind, John wanders the frozen surface, seeking to have himself and his story survive.

Vonnegut based the title character of God Bless You, Mr. Rosewater (1964), on an accountant he knew on Cape Cod, who specialized in clients in trouble and often had to comfort them. Eliot Rosewater, the wealthy son of a Republican senator, seeks to atone for his wartime killing of noncombatant firefighters by serving in a volunteer fire department, and by giving away money to those in trouble or need. Stress from a battle for control of his charitable foundation pushes him over the edge, and he is placed in a mental hospital. He recovers, and ends the financial battle by declaring the children of his county to be his heirs. Allen deemed God Bless You, Mr. Rosewater more "a cry from the heart than a novel under its author's full intellectual control", that reflected family and emotional stresses Vonnegut was going through at the time.

After spending almost two years at the writer's workshop at the University of Iowa, teaching one course each term, Vonnegut was awarded a Guggenheim Fellowship for research in Germany. By the time he won it, in March 1967, he was becoming a well-known Writer. He used the funds to travel in Eastern Europe, including to Dresden, where he found many prominent buildings still in ruins. At the time of the bombing, Vonnegut had not appreciated the sheer scale of destruction in Dresden; his enlightenment came only slowly as information dribbled out, and based on early figures he came to believe that 135,000 had died there.

After Slaughterhouse-Five was published, Vonnegut embraced the fame and financial security that attended its release. He was hailed as a hero of the burgeoning anti-war movement in the United States, was invited to speak at numerous rallies, and gave college commencement addresses around the country. In addition to briefly teaching at Harvard University as a lecturer in creative writing in 1970, Vonnegut taught at the City College of New York as a distinguished professor during the 1973–1974 academic year. He was later elected vice President of the National Institute of Arts and Letters, and given honorary degrees by, among others, Indiana University and Bennington College. Vonnegut also wrote a play called Happy Birthday, Wanda June, which opened on October 7, 1970 at New York's Theatre de Lys. Receiving mixed reviews, it closed on March 14, 1971. In 1972, Universal Pictures adapted Slaughterhouse-Five into a film which the author said was "flawless".

Vonnegut's difficulties materialized in numerous ways; most distinctly though, was the painfully slow progress he was making on his next novel, the darkly comical Breakfast of Champions. In 1971, Vonnegut stopped writing the novel altogether. When it was finally released in 1973, it was panned critically. In Thomas S. Hischak's book American Literature on Stage and Screen, Breakfast of Champions was called "funny and outlandish", but reviewers noted that it "lacks substance and seems to be an exercise in literary playfulness." Vonnegut's 1976 novel Slapstick, which meditates on the relationship between him and his sister (Alice), met a similar fate. In The New York Times's review of Slapstick, Christopher Lehmann-Haupt said Vonnegut "seems to be putting less effort into [storytelling] than ever before", and that "it still seems as if he has given up storytelling after all." At times, Vonnegut was disgruntled by the personal nature of his detractors' complaints.

In 1979, Vonnegut married Jill Krementz, a Photographer whom he met while she was working on a series about Writers in the early 1970s. With Jill, he adopted a daughter, Lily, when the baby was three days old. In subsequent years, his popularity resurged as he published several satirical books, including Jailbird (1979), Deadeye Dick (1982), Galápagos (1985), Bluebeard (1987), and Hocus Pocus (1990). In 1986, Vonnegut was seen by a younger generation when he played himself in Rodney Dangerfield's film Back to School. The last of Vonnegut's fourteen novels, Timequake (1997), was, as University of Detroit history professor and Vonnegut biographer Gregory Sumner said, "a reflection of an aging man facing mortality and testimony to an embattled faith in the resilience of human awareness and agency." Vonnegut's final book, a collection of essays entitled A Man Without a Country (2005), became a bestseller.

Vonnegut was an admirer of Jesus' Sermon on the Mount, particularly the Beatitudes, and incorporated it into his own doctrines. He also referred to it in many of his works. In his 1991 book Fates Worse than Death, Vonnegut suggests that during the Reagan administration, "anything that sounded like the Sermon on the Mount was socialistic or communistic, and therefore anti-American". In Palm Sunday, he wrote that "the Sermon on the Mount suggests a mercifulness that can never waver or fade." However, Vonnegut had a deep dislike for certain aspects of Christianity, often reminding his readers of the bloody history of the Crusades and other religion-inspired violence. He despised the Televangelists of the late 20th century, feeling that their thinking was narrow-minded.

Unless otherwise cited, items in this list are taken from Thomas F. Marvin's 2002 book Kurt Vonnegut: A Critical Companion, and the date in brackets is the date the work was first published:

In a 2006 Rolling Stone interview, Vonnegut sardonically stated that he would sue the Brown & Williamson tobacco company, the maker of the Pall Mall-branded cigarettes he had been smoking since he was twelve or fourteen years old, for false advertising. "And do you know why?" he said. "Because I'm 83 years old. The lying bastards! On the package Brown & Williamson promised to kill me." He died on the night of April 11, 2007 in Manhattan, as a result of brain injuries incurred several weeks prior from a fall at his New York brownstone home. His death was reported by his wife Jill. Vonnegut was 84 years old. At the time of his death, Vonnegut had written fourteen novels, three short story collections, five plays and five non-fiction books. A book composed of Vonnegut's unpublished pieces, Armageddon in Retrospect, was compiled and posthumously published by Vonnegut's son Mark in 2008.

Vonnegut has inspired numerous posthumous tributes and works. In 2008, the Kurt Vonnegut Society was established, and in November 2010, the Kurt Vonnegut Memorial Library was opened in Vonnegut's hometown of Indianapolis. The Library of America published a compendium of Vonnegut's compositions between 1963 and 1973 the following April, and another compendium of his earlier works in 2012. Late 2011 saw the release of two Vonnegut biographies, Gregory Sumner's Unstuck in Time and Charles J. Shields's And So It Goes. Shields's biography of Vonnegut created some controversy. According to The Guardian, the book portrays Vonnegut as distant, cruel and nasty. "Cruel, nasty and scary are the adjectives commonly used to describe him by the friends, colleagues, and relatives Shields quotes", said The Daily Beast's Wendy Smith. "Towards the end he was very feeble, very depressed and almost morose", said Jerome Klinkowitz of the University of Northern Iowa, who has examined Vonnegut in depth.

In 2011, NPR wrote, "Kurt Vonnegut's blend of anti-war sentiment and satire made him one of the most popular Writers of the 1960s." Vonnegut stated in a 1987 interview that, "my own feeling is that civilization ended in World War I, and we're still trying to recover from that", and that he wanted to write war-focused works without glamorizing war itself. Vonnegut had not intended to publish again, but his anger against the George W. Bush administration led him to write A Man Without a Country.

Vonnegut's works have, at various times, been labeled science fiction, satire and postmodern. He also resisted such labels, but his works do contain Common tropes that are often associated with those genres. In several of his books, Vonnegut imagines alien societies and civilizations, as is Common in works of science fiction. Vonnegut does this to emphasize or exaggerate absurdities and idiosyncrasies in our own world. Furthermore, Vonnegut often humorizes the problems that plague societies, as is done in satirical works. However, literary theorist Robert Scholes noted in Fabulation and Metafiction that Vonnegut "reject[s] the traditional satirist's faith in the efficacy of satire as a reforming instrument. [He has] a more subtle faith in the humanizing value of laughter." Examples of postmodernism may also be found in Vonnegut's works. Postmodernism often entails a response to the theory that the truths of the world will be discovered through science. Postmodernists contend that truth is subjective, rather than objective, as it is biased towards each individual's beliefs and outlook on the world. They often use unreliable, first-person narration, and narrative fragmentation. One critic has argued that Vonnegut's most famous novel, Slaughterhouse-Five, features a metafictional, Janus-headed outlook as it seeks both to represent actual historical events while problematizing the very notion of doing exactly that. This is encapsulated in the opening lines of the novel: "All this happened, more or less. The war parts, anyway, are pretty much true." This bombastic opening – "All this happened" – "reads like a declaration of complete mimesis" which is radically called into question in the rest of the quote and “[t]his creates an integrated perspective that seeks out extratextual themes [like war and traumra] while thematizing the novel's textuality and inherent constructedness at one and the same time.” While Vonnegut does use elements as fragmentation and metafictional elements, in some of his works, he more distinctly focuses on the peril posed by individuals who find subjective truths, mistake them for objective truths, then proceed to impose these truths on others.

Religion features frequently in Vonnegut's work, both in his novels and elsewhere. He laced a number of his speeches with religion-focused rhetoric, and was prone to using such expressions as "God forbid" and "thank God". He once wrote his own version of the Requiem Mass, which he then had translated into Latin and set to music. In God Bless You, Dr. Kevorkian, Vonnegut goes to heaven after he is euthanized by Dr. Jack Kevorkian. Once in heaven, he interviews 21 deceased celebrities, including Isaac Asimov, william Shakespeare, and Kilgore Trout—the last a fictional character from several of his novels. Vonnegut's works are filled with characters founding new faiths, and religion often serves as a major plot device, for Example in Player Piano, The Sirens of Titan and Cat's Cradle. In The Sirens of Titan, Rumfoord proclaims The Church of God the Utterly Indifferent. Slaughterhouse-Five sees Billy Pilgrim, lacking religion himself, nevertheless become a chaplain's assistant in the military and display a large crucifix on his bedroom wall. In Cat's Cradle, Vonnegut invented the religion of Bokononism.

The Science Fiction and Fantasy Hall of Fame inducted Vonnegut posthumously in 2015.