Maddox was born in London in 1969 to former Nature editor Sir John Maddox, a writer on science and nature, and Brenda Maddox, a biographer of Rosalind Franklin, W.B. Yeats, Nora Barnacle and several others. He has one sister, Bronwen, who became a journalist and is Chief Foreign Commentator of The Times as of 2008. Maddox enjoyed a privileged life during his childhood and youth, because of his father's position as editor of Nature, encountering some of the leading scientific thinkers of the day and enjoying dinners with figures such as James Watson and Sir Fred Hoyle.

Despite his family's background in science, Maddox was interested in the humanities while he attended Westminster School, an independent boys' school in London. Maddox went on to study English literature at Harvard University and graduated in 1992. He published his first and only article in the student newspaper The Harvard Crimson during his senior year. He won the undergraduate Thomas Temple Hoopes Prize for his senior thesis "on the use of adjectives in restaurant menus" titled Maltese: A Gastrosophic Theory of Reading. After graduation Maddox moved from Cambridge, Massachusetts to Moscow...where he worked for three weeks as the English-language editor of a Russian magazine...and then to New York City, where he spent two years working odd jobs, including hand-delivering celebrity invitations to local parties.

Maddox's freelance writing career began in 1994, when he became a book reviewer for The New York Times Book Review and The Washington Post, where he developed a reputation for writing scathing reviews that would later help him land a job as an editor at Spy magazine. Maddox described his book reviewing style as "pretty vicious", and quipped that he "was a frustrated, twenty-something guy, sitting in his bedroom venting existential rage on these nasty academics". His last book review for The Washington Post was in late 1996; however, he continued reviewing for The New York Times up until 1998, contributing only a couple of reviews thereafter.

At the beginning of the dot-com boom, Maddox found full-time work at an information technology company, where he worked for a year and a half.

In mid-1996, Maddox was hired as a senior editor at Spy magazine, a satirical monthly, in New York City. Spy had ceased publication in 1994 but was quickly resuscitated under new ownership by Sussex Publishers Inc., which reduced the magazine's frequency from ten to six issues a year. At Spy, Maddox was assisted by deputy editor Adam Lehner, a satirist. In December 1996, Maddox was promoted to editor-in-chief; his editorial team included Jared Paul Stern and, beginning in late 1997, future screenwriter William Monahan.

Maddox wanted to turn Spy into a national magazine rather than build on its legacy of covering stories that centered on New York. According to Maddox, two factors motivated the shift of target market. The magazine's past objects of satire, the "cheesy villains who anointed themselves as targets" in the 1980s, were no longer on the national stage. Meanwhile, the "sins of the '90s [were] those of a private, quiet cultivation of a sense of purity", and were harder to expose or ridicule.

In early 1998, Sussex Publishers increased Spy's frequency from six to nine issues a year in an effort to boost readership and ad pages. Spy's paid circulation continued to drop during Maddox's tenure, and in March 1998, the magazine once again ceased publication. Sussex's President and CEO John Colman concluded that "[despite the] great work by Bruno and his team, there just wasn't the [advertiser and consumer] acceptance that we need to make it financially viable". Maddox conceded that "a satirical magazine in New York in the late Nineties really had no function", because "everyone was being very modest and coy".

In 1999, Maddox sold the advance rights to his first novel, My Little Blue Dress, to a German publisher based on a five-page fax proposal he sent on the advice of his literary agent John Brockman. Within a week Brockman managed to sell the rights to the novel to publishers in an additional eight countries on the strength of the proposal alone. (Maddox had not yet written even an initial manuscript.)

My Little Blue Dress was published in 2001 by Viking Press, a Penguin Group imprint. The novel begins as a memoir of a hundred-year-old woman, but several chapters later reveals itself to be a spoof of the genre. The protagonist is a fictional Bruno Maddox who is desperately attempting to create a forgery of an old woman's memoir in a single night. Several book reviewers avoided spoiling the novel's satire but others gave away its premise, reasoning that the publisher "reveal[s] all on the book jacket anyway". The novel's intrigue lies in the mysterious reason compelling the fictional Maddox to forge a memoir.

Critics applauded My Little Blue Dress but also expressed some reservations. For example, Salon.com's Maria Russo cautioned that the novel "is one of those 'don't try this at home' literary experiments that could easily have turned into an unreadable, pretentious disaster", but concluded that Maddox "pulls it off with a kind of fearless pizzazz". The New York Times' Emily Barton conceded that "for all its blunders", Maddox delivers "a winsome and vastly entertaining novel".

In an interview, Maddox praised Bret Easton Ellis’s 1991 novel American Psycho, stating that he drew inspiration from protagonist Patrick Bateman's long-winded monologues about Phil Collins, restaurants, clothes, and how to remove blood from his carpets.

In 2001, Maddox promoted his first novel on a joint book tour billed as the "Minor Novelists Tour" with his friend William Monahan, another former Spy editor, but it was interrupted by the 9/11 attacks. Monahan's A Trifle was also published by a Penguin imprint. Several years later, Maddox gave some indication that he was working on a film adaptation of My Little Blue Dress,A note at the end of several of Maddox's book reviews read, "Bruno Maddox is adapting his novel 'My Little Blue Dress' for the screen." See Maddox's review of P. J. O'Rourke's Peace Kills: America's Fun New Imperialism (New York Post, 6 June 2004) and his review of George Hagen's The Laments (New York Post, 27 June 2004).