McInerney studied writing with Raymond Carver and once worked as a fact-checker at The New Yorker. He achieved fame with his first published novel Bright Lights, Big City. Published in 1984, the novel was unique at the time for its depiction of cocaine culture in second-person narrative. The title is taken from a 1961 blues song by Jimmy Reed. The novel established McInerney’s reputation as part of a new generation of writers. Labelled the ‘literary brat pack' in a 1987 article in the Village Voice, McInerney, Bret Easton Ellis and Tama Janowitz were presented as the new face of literature: young, iconoclastic and fresh. Five novels followed in rapid succession: Ransom, Story of My Life, Brightness Falls, The Last of the Savages and Model Behavior.

After the success of Bright Lights, Big City, publishers started looking for similar works about young people in urban settings. Ellis's Less Than Zero, published in 1985, was promoted as following McInerney’s example. McInerney, Ellis and Janowitz were based in New York City and their lives there were regular literary themes, chronicled by New York media.

Ellis used McInerney's character, Alison Poole (Story of My Life), in his novels American Psycho and Glamorama. McInerney revealed that the character of Alison Poole is based upon his former girlfriend, Rielle Hunter, then known as Lisa Druck. He described the character as "cocaine addled," and "sexually voracious" but also treated her with some sympathy. McInerney's roman a clef opened a prescient glimpse into the notorious horse murders scandal, which did not become known to the public until 1992, when Sports Illustrated magazine published a confession from the man who had murdered Lisa Druck's horse at her father's behest, in order to claim the insurance on its life. Hunter, who has remained in contact with McInerney as friend, had an affair in 2007 with then-Presidential candidate John Edwards, which resulted in the birth of a daughter, Quinn. Edwards at first denied that the baby was his, but admitted that he is the father of Quinn in January 2010.

McInerney also has a cameo role in Ellis's Lunar Park, attending the Halloween party Bret hosts at his house. It was later revealed that McInerney was not pleased with his representation in the novel.

Throughout his career McInerney has struggled against the strong, almost indelible, image of himself as both the author and protagonist of Bright Lights, Big City. He recently appeared at Williams College as the Commencement speaker for the Class of 2010.

His first wife was fashion model Linda Rossiter, and his second wife was writer Merry Reymond; for four years he lived with fashion model Marla Hanson. He has twins (Maisie and John Barrett McInerney III, born in 1994) with his former third wife, jewelry designer and writer Helen Bransford. He is currently married to heiress Anne Hearst.

Fiction

• Bright Lights, Big City (1984)
• Ransom (1985)
• Story of My Life (1988)
• Brightness Falls (1992)
• The Last of the Savages (1997)
• Model Behavior (1998)
• The Good Life (2006)
• How It Ended (short story collection, US) (2009) / The Last Bachelor (short story collection, UK) (2009)

Nonfiction

• Adventures in the Wine Cellar (2000)
• Adventures in Wine (2006)

Film

• Bright Lights, Big City adapted in 1988, screenplay McInerney, directed by James Bridges, starring Michael J. Fox, Kiefer Sutherland, Phoebe Cates

Short stories

• "Everything is Lost" (2009, Sunday Times 4th Jan, online text)
• How It Ended: New and Collected Stories (2009 331 pp. Alfred A. Knopf, $25.95). Titles, with descriptions from The New York Times book review by Sam Tanenhaus, included:
• "Con Doctor," in which a doctor's lady friend, "a recovering alcoholic, brassy and voluptuous ... looked like someone who would be dating a pro athlete, or a guy with a new Ferrari who owned a chain of fitness centers;
• "My Public Service," in which he explores one of "the many varieties of the strangling embrace, [with] star-struck political hirelings reduced to pimping for a philandering senator;
• "The Madonna of Turkey Season": "Irish-American brothers locked in competitive mother-love";
• "Invisible Fences": "a Bible Belt couple whose sexual dysfunction degrades them into sick rituals of voyeurism";
• "Smoke": "[I]ntroduced Russell and Corrine Calloway, the Manhattan couple-with-everything whose marital vicissitudes animate McInerney’s two most ambitious novels, Brightness Falls and its sequel, The Good Life."
• "In the North-West Frontier Province": "[E]erily predicts our current postterrorist age[;] ... a glimpse of hell, set in the parched hilly borderlands between Afghanistan and Pakistan.