Clark was born in Tulsa, Oklahoma. He learned photography at an early age. His mother was an itinerant baby Photographer, and he was enlisted in the family Business from the age of 13. His father was a traveling sales manager for the Reader Service Bureau, selling books and magazines door-to-door, and was rarely home. In 1959, Clark began injecting amphetamines with his friends.

Routinely carrying a camera, from 1963 to 1971 Clark produced pictures of his drug-shooting coterie that have been described by critics as "exposing the reality of American suburban life at the fringe and ... shattering long-held mythical conventions that drugs and violence were an experience solely indicative of the urban landscape."

In 1964, he moved to New York City to freelance, but was drafted within two months to serve in the Vietnam War. His experiences there led him to publish the 1971 book Tulsa, a photo documentary illustrating his young friends' drug use in black and white.

His follow-up was Teenage Lust (1983), an "autobiography" of his teen past through the images of others. It included his family photos, more teenage drug use, graphic pictures of teenage sexual activity, and young male hustlers in Times Square, New York City. Clark constructed a photographic essay titled "The Perfect Childhood" that examined the effect of media in youth culture. His photographs are part of public collections at several art museums including the Whitney Museum of American Art, and the Museum of Fine Arts, Boston.

In 1993, Clark directed Chris Isaak's music video "Solitary Man". This experience developed into an interest in film direction. After publishing other photographic collections, Clark met Harmony Korine in New York City and asked Korine to write the screenplay for his first feature film Kids, which was released to controversy and mixed critical reception in 1995. Clark continued directing, filming a handful of additional independent feature films in the several years after this.

In Kids (1995), his most widely known film, boys portrayed as being as young as 12 are shown to be casually drinking alcohol and using other drugs. The film received an NC-17 rating, and was later released without a rating when Disney bought Miramax.

In 2001, Clark shot three features Bully, Ken Park and Teenage Caveman over a span of nine months, As of 2017 they are his last films to feature professional actors.

In 2002, Clark spent several hours in a police cell after punching and trying to strangle Hamish McAlpine, the head of Metro Tartan, the UK distributor for Clark's film Ken Park. According to McAlpine, who was left with a broken nose, the incident arose from an argument about Israel and the Middle East, and he claims that he did not provoke Clark.

Ken Park is a more sexually and violently graphic film than Kids, including a scene of auto-erotic asphyxiation and ejaculation by an emotionally rattled high-school boy (portrayed by James Ransone, then in his early 20s). As of 2015, it has not been widely released or distributed in the United States.

In a 2016 interview, Clark discussed his lifelong struggle with drug abuse, although stating he maintained total sobriety while filmmaking. Clark stated that his films were made in periods of complete sobriety. He confessed that the only exception made to his practice of abstinence while filming was Marfa Girl 2. Clark explained that while filming that movie he used opiates for pain due to double knee replacement surgery.