Irving's biological father, whom he never met, had been a pilot in the Army Air Forces and, during World War II, was shot down over Burma in July 1943, but somehow survived. (The incident was incorporated into his novel The Cider House Rules.) Irving did not find out about his father's heroism until 1981, when he was almost 40 years old.

In 1964, Irving married Shyla Leary, whom he had met at Harvard in 1963 while taking a summer course in German, before traveling to Vienna, Austria with IES Abroad. They have two sons, Colin and Brendan. The couple divorced in the early 1980s. In 1987, he married Janet Turnbull, who had been his publisher at Bantam-Seal Books and is now one of his literary agents. They have a son, Everett. Irving has homes in Vermont, Toronto, and Pointe au Baril.

Irving's career began at the age of 26 with the publication of his first novel, Setting Free the Bears (1968). The novel was reasonably well reviewed but failed to gain a large readership. In the late 1960s, he studied with Kurt Vonnegut at the University of Iowa Writers' Workshop. His second and third novels, The Water-Method Man (1972) and The 158-Pound Marriage (1974), were similarly received. In 1975, Irving accepted a position as assistant professor of English at Mount Holyoke College.

Frustrated at the lack of promotion his novels were receiving from his first publisher, Random House, Irving offered his fourth novel, The World According to Garp (1978), to Dutton, which promised him stronger commitment to marketing. The novel became an international bestseller and cultural phenomenon. It was a finalist for the National Book Award for Fiction in 1979 (eventually going to Tim O'Brien for Going After Cacciato) and its first paperback edition won the Award next year. Garp was later made into a film directed by George Roy Hill and starring Robin Williams in the title role and Glenn Close as his mother; it garnered several Academy Award nominations, including nominations for Close and John Lithgow. Irving makes a brief cameo in the film as an official in one of Garp's high school wrestling matches.

The World According to Garp was among three books recommended to the Pulitzer Advisory Board for consideration for the 1979 Award in Fiction in the Pulitzer Jury Committee report, although the award was given to The Stories of John Cheever (1978).

Irving has had four novels reach number one on the bestseller list of The New York Times: The Hotel New Hampshire (September 27, 1981), which stayed number one for seven weeks, and was in the top 15 for over 27 weeks; The Cider House Rules (June 16, 1985); A Widow for One Year (June 14, 1998); and The Fourth Hand (July 29, 2001).

In 1985, Irving published The Cider House Rules. An epic set in a Maine orphanage, the novel's central topic is abortion. Many drew parallels between the novel and Charles Dickens' Oliver Twist (1838). Irving's next novel was A Prayer for Owen Meany (1989), another New England family epic about religion set in a New England boarding school and in Toronto, Ontario. The novel was influenced by The Tin Drum (1959) by Günter Grass, and the plot contains further allusions to The Scarlet Letter (1850) by Nathaniel Hawthorne and the works of Dickens. In Owen Meany, Irving for the first time examined the consequences of the Vietnam War—particularly mandatory conscription, which Irving avoided because he was a married father when of age for the draft. Owen Meany became Irving's best selling book since Garp.

Since the publication of Garp made him independently wealthy, Irving has sporadically accepted short-term teaching positions (including one at his alma mater, the Iowa Writers' Workshop) and served as an assistant coach on his sons' high school wrestling teams. (Irving was inducted into the National Wrestling Hall of Fame as an "Outstanding American" in 1992.) In addition to his novels, he has also published Trying to Save Piggy Sneed (1996), a collection of his writings including a brief memoir and unpublished short fiction, My Movie Business, an account of the protracted process of bringing The Cider House Rules to the big screen, and The Imaginary Girlfriend, a short memoir focusing on writing and wrestling. In 2010, Irving revealed that he and Tod "Kip" Williams, Director and Writer of The Door in the Floor (2004), were co-writing a screenplay for an adaptation of A Widow for One Year (1998).

Irving returned to Random House for his next book, A Son of the Circus (1995). Arguably his most complicated and difficult book, and a departure from many of the themes and location settings in his previous novels, it was dismissed by critics but became a national bestseller on the strength of Irving's reputation for fashioning literate, engrossing page-turners. Irving returned in 1998 with A Widow for One Year, which was named a New York Times Notable Book.

In recent years, his four most highly regarded novels, The World According to Garp, The Cider House Rules, A Prayer for Owen Meany, and A Widow for One Year, have been published in Modern Library editions. Owen Meany was adapted into the 1998 film Simon Birch (Irving required that the title and character names be changed because the screenplay's story was "markedly different" from that of the novel; Irving is on record as having enjoyed the film, however). In 2004, a portion of A Widow for One Year was adapted into The Door in the Floor, starring Jeff Bridges and Kim Basinger.

Soon afterward, Irving wrote My Movie Business, a memoir about his involvement in creating the film version of The Cider House Rules. After its publication in 1999, Irving appeared on the CBC Television program Hot Type to promote the book. During the interview, Irving criticized bestselling American author Tom Wolfe, saying Wolfe "can't write", and that Wolfe's writing makes Irving gag. Wolfe appeared on Hot Type later that year, calling Irving, Norman Mailer, and John Updike his "three stooges" who were panicked by his newest novel, A Man in Full (1998).

On June 28, 2005, The New York Times published an article revealing that Until I Find You (2005) contains two specifically personal elements about his life that he had never before discussed publicly: his sexual abuse at age 11 by an older woman, and the recent entrance in his life of his biological father's family.

Irving was diagnosed with prostate cancer in 2007 and subsequently had a radical prostatectomy.

In a New York Magazine interview in 2009, Irving stated that he had begun work on a new novel, his 13th, based in part on a speech from Shakespeare's Richard II. Simon & Schuster published the novel, titled In One Person (2012), taking over from Random House. In One Person has a first-person viewpoint, Irving's first such narrative since A Prayer for Owen Meany (Irving decided to change the first-person narrative of Until I Find You to third person less than a year before publication). In One Person features a 60-year-old, bisexual protagonist named william, looking back on his life in the 1950s and '60s. The novel shares a similar theme and concern with The World According to Garp, which was Irving says, in part about "people who hate you for your sexual differences."

In 2010, Irving confirmed that he is a second cousin of Amy Bishop, a former assistant professor at the University of Alabama in Huntsville, who is serving a life sentence for shooting six colleagues, killing three, during a department meeting on February 12, 2010.

On June 10, 2013, Irving announced his next novel, his 14th, titled Avenue of Mysteries, named after a street in Mexico City. In an interview the previous year, he had revealed the last line of the book: "Not every collision course comes as a surprise."

On December 19, 2014, John Irving posted a message on the Facebook page devoted to him and his work that he had "finished 'Avenue of Mysteries.' It is a shorter novel for me, comparable in length to 'In One Person.'" Irving speculated that "if everything remains on schedule, the English-language editions should be published in fall 2015." Simon & Schuster published the book in November, 2015.

On November 3, 2015, Irving revealed that he'd been approached by HBO and Warner Brothers to reconstruct The World According to Garp as a miniseries. He described the project as being in the early stages.

In an interview with Mike Kilen for The Des Moines Register, published on October 26, 2017, John Irving revealed that the title of his new novel-in-progress is Darkness As a Bride. The title comes from lines in Shakespeare's play, Measure for Measure: "If I must die, / I will encounter darkness as a bride, / and hug it in mine arms."