Hornby published his first book in 1992, a collection of essays about American Writers such as Tobias Wolff and Ann Beattie, titled Contemporary American Fiction. Hornby's second book, Fever Pitch, also published in 1992, is an autobiographical story detailing his fanatical support for Arsenal Football Club. As a result, Hornby received the william Hill Sports Book of the Year Award. In 1997, the memoir was adapted for film in the UK, and in 2005 an American remake was released, following Jimmy Fallon's character's obsession with the Boston Red Sox, a baseball team. With the book's success, Hornby began to publish articles in the Sunday Times, Time Out and the Times Literary Supplement, in addition to his music reviews for the New Yorker.

Hornby has been married twice. He and his first wife have one son, born in 1993, who has autism. Hornby's second wife is Producer Amanda Posey. They have two sons, born in 2003 and 2005. Hornby's sister, Writer Gill Hornby, is married to Writer Robert Harris.

Several of Hornby's books have made the jump from page to screen. Hornby wrote the screenplay for the first, a 1997 British adaptation of Fever Pitch, starring Colin Firth. It was followed by High Fidelity in 2000, starring John Cusack; this adaptation was notable in that the action was shifted from London to Chicago. After this success, About a Boy was quickly picked up, and released in 2002, starring Hugh Grant. An Americanized Fever Pitch, in which Jimmy Fallon plays a hopelessly addicted Boston Red Sox fan who tries to reconcile his love of the game with that of his girlfriend (Drew Barrymore), was released in 2005. Johnny Depp purchased film rights to the book A Long Way Down before it was published.

His second novel, About a Boy, published in 1998, is about two "boys" — Marcus, an awkward yet endearing adolescent from a single-parent family, and the free-floating, mid-30s Will Freeman, who overcomes his own immaturity and self-centeredness through his growing relationship with Marcus. Hugh Grant and Nicholas Hoult starred in the 2002 film version. In 1999, Hornby received the E. M. Forster Award of the American Academy of Arts and Letters.

Hornby's next novel, How to Be Good, was published in 2001. The female protagonist in the novel explores contemporary morals, marriage and parenthood. It won the W.H. Smith Award for Fiction in 2002.

Part of the money he earned with his next book, Speaking with the Angel in 2002, was donated to TreeHouse, a charity for children with autism, the disorder that affects Hornby's own son. He was Editor of the book, which contained twelve short stories written by his friends. He also contributed to the collection with the story "NippleJesus".

Hornby has also written essays on various aspects of popular culture, and in particular, he has become known for his writing on pop music and mix tape enthusiasts. Since 2003, he has written a book review column, "Stuff I've Been Reading", for the monthly magazine The Believer; all of these articles are collected between The Polysyllabic Spree (2004), Housekeeping vs. The Dirt (2006), Shakespeare Wrote for Money (2008), and More Baths Less Talking (2012).

Hornby's novel A Long Way Down was published in 2005, with a film version of this book released in 2014. It was on the shortlist for the Whitbread Novel Award. Hornby has also edited two sports-related anthologies: My Favourite Year and The Picador Book of Sports Writing.

High Fidelity was also the basis for a 2006 eponymous musical that shifted the action to Brooklyn; its book is by David Lindsay-Abaire, with lyrics by Amanda Green and music created by Tom Kitt. The production ran for a month in Boston, then moved to Broadway, closing after 18 previews and 14 regular performances.

Hornby's book Slam was published on 16 October 2007; it is his first novel for young adults and was recognized as a 2008 ALA Best Books for Young Adults. The protagonist of Slam is a 16-year-old Skateboarder named Sam whose life changes drastically when his girlfriend gets pregnant.

In 2009, Hornby adapted an autobiographical memoir by the Journalist Lynn Barber for the screen as An Education, a feature film starring Peter Sarsgaard and Carey Mulligan. He was nominated for an Academy Award for Best Adapted Screenplay and for two BAFTAs for writing the screenplay.

Hornby has also had extensive collaboration with American singer/songwriter Ben Folds. Their album Lonely Avenue was released in September 2010. Folds wrote the music, with Hornby contributing lyrics. Prior to the album's release, the single "Picture Window" was released on Ben Folds' website. A bootleg version of a song about Levi Johnston written by Hornby and Folds and performed by Folds, appeared on the internet.

Hornby discussed his bouts of depression in 2012 on the BBC Radio 4 broadcast of "Fever Pitched: Twenty Years On".

About a Boy was adapted for television and aired on NBC from February 22, 2014 to February 17, 2015. The show was developed by Jason Katims and it is the second adaptation based on the 1998 novel. The series stars David Walton, Minnie Driver and Benjamin Stockham,

In 2015, he wrote the script for the film Brooklyn, an adaptation of Colm Tóibín's novel of the same name. Tim Robey of The Daily Telegraph said it was "his strongest work ever as a screenwriter". According to Metacritic, the film is on eighty "top 10" lists for 2015. He was nominated for his second Oscar for writing the screenplay.

In 2016, Hornby adapted Nina Stibbe's book Love, Nina: Despatches from Family Life into a television series. Love, Nina received its debut on BBC One on 20 May 2016, and ran for five episodes.