Korine was born in Bolinas, California and raised in Nashville, Tennessee, to a Jewish family. He is the son of Eve and Sol Korine. His father was a tapdancer and produced documentaries for PBS in the 1970s about an "array of colorful Southern characters"; he would take Korine to carnivals and circuses and taught him how to use a Bolex camera. As a child, Korine watched movies with his father, who rented Buster Keaton films and took him to see Even Dwarfs Started Small (1970) in the theater. Korine reminisces, "I knew there was a poetry in cinema that I had never seen before that was so powerful." As a child, Korine changed his name from "Harmony" and went by "Harmful," as he thought it made him sound tougher when he got in fights. Korine spent his childhood in Nashville, attending Hillsboro High School before moving to New York City to live with his grandmother. Korine also spent some time living with his parents in a commune, which helped to inspire the commune setting of Mister Lonely. As a teenager, Korine frequented revival theaters, watching classic films by John Cassavetes, Werner Herzog, Jean-Luc Godard, Rainer Werner Fassbinder, and Alan Clarke. In an interview with Bruce LaBruce, Korine briefly mentioned that he studied Business Administration in college. Other sources state that he studied Dramatic Writing at Tisch School of the Arts at New York University for one semester before dropping out to pursue a career as a professional Skateboarder.

Korine met Chloë Sevigny in Washington Square Park in New York City during her senior year of high school in 1993. The two became close friends, which resulted in her being cast in the low-budget independent film Kids (1995). They had a relationship that ended in the early 2000s. He is now married to Actress Rachel (Simon) Korine, with whom he has two children.

Korine has also published a number of books. In 1995 a screenplay for Kids was published by Grove Press, followed by a collection of the screenplays for Gummo, Julien Donkey-Boy, and Jokes in Collected Screenplays, published by Faber and Faber in 2002. In 2008 the screenplay for Mister Lonely was released by Swiss publisher Nieves with photographs by Rachel Korine and Brent Stewart. The majority of these books differ substantially from the movies eventually produced.

In 1997, Korine's favorite Writers were listed as James Thurber, S. J. Perelman, and Flannery O'Connor. Korine has noted British filmmaker Alan Clarke as an influence.

In 1998 Korine published a book entitled A Crack Up at the Race Riots, an experimental novel, described as his attempt to write "the Great American Choose Your Own Adventure novel" in his appearance on the Late Show with David Letterman. Korine was eventually banned from Letterman's show after he was caught going through Meryl Streep's purse after breaking into her dressing room. In November 2008, Drag City published a collection of his fanzines called The Collected Fanzines with skateboarder/writer Mark Gonzalez. 2009 sees Korine returning to the collaborative zine process alongside fellow avant-garde Artist Noel Sinclair Boyt.

In a 1999 Dazed and Confused magazine article, Korine listed his top ten films as: Pixote by Hector Babenco, Badlands and Days of Heaven by Terrence Malick, Fat City by John Huston, Stroszek by Werner Herzog, The Killing of a Chinese Bookie and A Woman Under the Influence by John Cassavetes, McCabe and Mrs. Miller by Robert Altman, Out of the Blue by Dennis Hopper and Hail Mary by Jean-Luc Godard.

In 2000 The Devil, The Sinner, and His Journey premiered, which featured Korine in black metal corpsepaint as O.J. Simpson and Johnny Depp as Kato Kaelin.

Korine has directed a number of music videos for artists such as Sonic Youth, Cat Power and Will Oldham (e.g., No More Workhorse Blues). In addition, he sang on Oldham's "Ease Down The Road", and co-authored the lyrics of Björk's musical composition "Harm of Will" from her album Vespertine (2001). In 1999 Korine and Brian Degraw of Gang Gang Dance released a music CD SSAB Songs. "I don't really know what it sounds like", Korine explained to i-D magazine. "I only listened to it once. I think it's the kind of album I'd only Listen to once". The tracks labeled "Harmony" on Songs in A&E are named after Korine by Jason Pierce of Spiritualized, who also made the Soundtrack to Mister Lonely. "Harmony Korine" is the lead track on the solo album Insurgentes by Porcupine Tree lead singer Steven Wilson. He has also directed a music video for "Gold on the Ceiling" by The Black Keys, from their album El Camino. He also co-wrote the song "Florida Kilos" with Lana Del Rey and Dan Auerbach, which is featured on the deluxe edition of Del Rey's album Ultraviolence.

In 2002, Larry Clark made Ken Park, based on a script Korine had written several years earlier. The film, another adult tale of youth gone awry, was not distributed in the United States. At the time of its release, Clark and Korine had long since parted ways, and Korine had no involvement in its production.

In 2003, he made the television documentary Above the Below about his friend and collaborator David Blaine and his 44-day stunt in a park over the bank of River Thames in London inside a suspended plexiglas box. A documentary commissioned by Sky Television and Channel 4, it also includes jokes, visual poetry, and music. In addition, Korine has worked with Blaine on a number of Blaine's specials.

Korine also appeared in the 2007 documentary film Beautiful Losers in which his life and career were one of the foci of the film, along with other artists such as Mike Mills, Shepard Fairey, Margaret Kilgallen, Jo Jackson and Barry McGee. In the documentary, Korine discusses his motivation as an Artist and filmmaker, as well as his inspiration for creating films he has never seen. Footage also appears from one of Korine's rare, early, and untitled short films, which preceded his work on Kids.

In 2008 Harmony Korine was signed to MJZ for worldwide commercial representation.

Korine released a number of photographic collections, usually in conjunction with gallery exhibits. In 1998 he published The Bad Son in conjunction with Taka Ishii gallery in Tokyo, documenting his various photo shoots with Macaulay Culkin. In 2002, Pass the Bitch Chicken was released, a collaboration with Artist Christopher Wool, which consists of Korine's photographs heavily edited by Korine and Wool. In 2009 he published Pigxote in conjunction with the Vanderbilt University Fine Arts Gallery and released by Nieves. The university describes the exhibition, which ran through February 26, 2009, as culling "together a number of photographs from Korine’s private files in order to reveal a side of the artist’s creative process that remains largely unexamined. Depicting an unnamed, mysterious young girl moving through a televised landscape of shifting contexts, Pigxote further illustrates Korine’s interest in replacing plot lines and expected narrative tropes with intuitively arranged “experiential moments.” They also provide a unique insight into the poetic mind of Nashville’s most compelling prodigal son." Most recently his works were presented in a 2003 exhibition at agnès b's Galerie du jour in Paris, with whom Korine has often been associated. In 2010, Korine collaborated with New York Visual Artist Bill Saylor on the book Ho Bags. The book consists of drawing and paintings in which Korine and Saylor drew over each other's works. In 2011 Korine collaborated with the New York brand Supreme, releasing a set of two skateboard decks featuring original artworks by Korine.

In March 2011, Korine released a short film entitled Umshini Wam, which is a popular Zulu struggle song meaning "bring me my machine gun". The film starred Ninja and Yo-Landi of Die Antwoord. In September 2011, Korine released a short film entitled Snowballs, sponsored by the Proenza Schouler fashion label.

Korine's next project was the crime drama Spring Breakers, which was produced in 2012 in Florida, and starred James Franco, Selena Gomez, Vanessa Hudgens, Ashley Benson, and Korine's wife, Rachel Korine. In looking at early scenes being filmed and in speaking toward the plot, cast, and earlier works of the filmmaker, Indiewire wrote "this might be the weirdest movie the Director has ever made simply by nature of being totally unlike his previous work." "That Mr. Korine appears to be having it both (or many) ways may seem like a cop-out, but only if you believe that the role of the Artist is to be a didact or a scold." wrote The New York Times. Principal filming wrapped up on March 30, 2012. The film was selected to compete for the Golden Lion at the 69th Venice International Film Festival. Spring Breakers received its world premiere at the 2012 Venice International Film Festival, and later was shown at the Toronto International Film Festival before being released to the general public in March 2013.

On the current state of cinema, Korine comments, "When I look at the history of film – the early commercial narrative movies directed by D.W. Griffith, say – and then look at where films are now, I see so little progression in the way they are made and presented, and I'm bored with that. Film can be so much more."

Korine directed the video clip "Needed Me" by Rihanna which was released on April 21, 2016. In the same year, Korine directed a Supreme commercial starring Rapper Gucci Mane (who had previously appeared in Spring Breakers), and appeared in the music video for Gucci Mane and Travis Scott's single Last Time.

The opening song on British Progressive rock musician Steven Wilson’s solo debut album Insurgentes is called "Harmony Korine".