Irving's career began at the age of 26 with the publication of his first novel, Setting Free the Bears. 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 and The 158-Pound Marriage, were similarly received. At around this time, 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, and was a finalist for the American Book Award (now the National Book Award) for hardcover fiction in 1979 (the award went to Tim O'Brien for Going After Cacciato). Garp won the National Book Foundation's award for paperback fiction the following 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.

Though it is not a widely known fact, The World According to Garp was, along with "Continental Drift" by Russell Banks, considered a finalist for the Pulitzer Prize in 1979, which was awarded to The Stories of John Cheever.

Garp transformed Irving from an obscure, academic literary writer to a household name, and his subsequent books were bestsellers. The first was The Hotel New Hampshire (1981), which sold well despite mixed reviews from critics. Like Garp, the novel was quickly made into a film, this time directed by Tony Richardson and starring Jodie Foster, Rob Lowe, and Beau Bridges.

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's Oliver Twist. Irving's next novel was A Prayer for Owen Meany, another New England family epic about religion set in a New England boarding school. The novel was influenced by The Tin Drum by Günter Grass, The Scarlet Letter 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, and is now a frequent feature on high school English reading lists.

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.

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 1999, after nearly ten years in development, Irving's screenplay for The Cider House Rules was made into a film directed by Lasse Hallström, starring Michael Caine, Tobey Maguire, Charlize Theron, and Delroy Lindo. Irving also has a cameo appearance as the disapproving stationmaster. The film was nominated for several Academy Awards, including Best Picture, and earned Irving an Academy Award for Best Adapted Screenplay.

Soon after, Irving wrote My Movie Business, a memoir about his involvement in creating the film version of The Cider House Rules. After its publication, 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 his 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.

When The Fourth Hand was published in 2001 it became a bestseller. A Sound Like Someone Trying Not to Make a Sound, a children's story originally included in A Widow for One Year, was published as a book with illustrations by Tatjana Hauptmann in 2004. Irving's novel, Until I Find You, was released on July 12, 2005.

On June 28, 2005, The New York Times published an article revealing that Until I Find You contains two specifically personal elements about his life that he has 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.

In his most recent novel, Last Night in Twisted River, published in 2009, Irving's central character is a novelist with "a career that teasingly follows Irving's own," as one journalist put it (e.g., including the aforementioned reference to Irving's own mandatory conscription).

Since the publication of Garp made him independently wealthy, Irving has been able to concentrate solely on fiction writing as a vocation, sporadically accepting short-term teaching positions (including one at his alma mater, the Iowa Writers' Workshop) and serving 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, 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 recent years, his three most highly regarded novels, The World According to Garp, The Cider House Rules, and A Prayer for Owen Meany, have been published in Modern Library editions. Owen Meany was adapted into the 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.

In a New York Magazine interview in 2009, Irving stated that he has begun work on a new novel, based, in part, on a speech from a play by Shakespeare, "Richard II." The novel is tentatively titled, "In One Person."

Recurring themes, symbols or character types in Irving's work include New England, prostitutes, wrestling, Vienna, Iowa, bears, deadly accidents, a main character and/or supporting characters who are writers of some sort (novelists, journalists, children's book authors, diarists, family historians, etc.), a main character dealing with an absent or unknown parent, a main character who is involved in film making, sexual relationships between young men and older women and other variations in sexual relations. Severing of body parts (tongue, finger, other) appears in several novels.

Irving has often used the literary technique of a story within a story.

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. They had two sons, Colin and Brendan, and 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 teenage son, Everett. Irving has homes in Vermont, Toronto, and Pointe au Baril.

Irving's biological father, who 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 survived (an incident incorporated into the novel The Cider House Rules). Irving did not find out about his father's heroism until 1981.

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

In 2010 Irving confirmed that he is a second cousin of Amy Bishop, an assistant professor at the University of Alabama in Huntsville who is facing murder charges after allegedly shooting six colleagues, killing three, during a department meeting on February 12.

• "The building of the architecture of a novel...the craft of it...is something I never tire of."

• "In this way, in increments both measurable and not, our childhood is stolen from us...not always in one momentous event but often in a series of small robberies, which add up to the same loss."

• "I spend about two to three months planning the path of the book in my head before I write the last sentence of the novel. From there I work back to the beginning. From the day I think of the last sentence to the book's publication date, not more than a semicolon has changed."

• [on his process for writing novels:] "I can't imagine what the first sentence is, I can't imagine where I want the reader to enter the story, if I don't know where the reader is going to leave the story. So once I know what the last thing the reader hears is, I can work my way backward, like following a roadmap in reverse."

• "A reader told me recently, in London, said that ‘well, I read that you write the last sentence first, so I always read your last sentence first.’ And I said, ‘oh, no, you're not supposed to do that.’"

• "Ted Seabrooke, my wrestling coach, had a kind of Nietzschean effect on me in terms of not just his estimation of my limited abilities, but his decidedly philosophical stance about how to conduct your life, what you should do to compensate for your limitations. This was essential to me, both as a student...and not a good one...and as a wrestler who was not a natural athlete but who had found something he loved."

• "When I finally write the first sentence, I want to know everything that happens, so that I am not inventing the story as I write it - rather, I am remembering a story that has already happened."

• "I feel more a part of the wrestling community than I feel I belong to the community of arts and letters. Why? Because wrestling requires even more dedication than writing because wrestling represents the most difficult and rewarding objective that I have ever dedicated myself to; because wrestling and wrestling coaches are among the most disciplined and self-sacrificing people I have ever known."

• "As a child, when something is denied you...when there is a subject that is never spoken of...you pretend it's for the best. But when I was denied information about someone as important as my actual father, I compensated for this loss by inventing him."

• "The characters in my novels, from the very first one, are always on some quixotic effort of attempting to control something that is uncontrollable...some element of the world that is essentially random and out of control."

• "When I feel like being a director, I write a novel."

• "Whatever I write, no matter how gray or dark the subject matter, it's still going to be a comic novel."

• (What he calls his incredibly popular novel "The World According to Garp"): "An artfully-disguised soap opera."

• (In reference to Vermont's Act 60): "This is Marxism. It's leveling everything by decimating what works ... It's that vindictive 'We've suffered, and now we're going to take money from your kid and watch you squirm'... There's a minority which is an open target in this country which no one protects, and that's rich people"

• "I don't go out of my way to find or invent things that are bizarre. It just seems to me that I notice more and more how commonplace the bizarre is."

• "I write repeatedly...against my will...of those things I fear most happening. Losing a loved one, losing a parent, losing a child. I'm in terror of losing a child. It's never happened to me, but I am clearly compelled to write about it over and over again, and in a way I think, psychologically at least, this says more about me autobiographically as a novelist than the fact that Danny Angel goes to the Iowa Writers Workshop and has Kurt Vonnegut as a teacher, which I also did."