Clark was born in New Orleans in 1939, but grew up in Birmingham, Alabama, and later moved to Fort Lauderdale, Florida. He grew up poor, as his father died during his childhood and his mother was a barmaid. After attending Catawba College majoring in philosophy, Clark won a football scholarship to Hillsdale College in Michigan, where he played quarterback. Eventually he studied theater at the University of Miami, turning down offers to play professional football. He did briefly play semi-pro for the Fort Lauderdale Black Knights.

Clark's career began in the horror genre in the early 1970s. His first film, Children Shouldn't Play with Dead Things (1972), was a blend of comedy and graphic horror.

Clark and his collaborator for this film, Screenwriter and makeup Artist Alan Ormsby, would revisit the zombie subgenre in 1972's Deathdream, also known by its alternate title, Dead of Night, a Vietnam War allegory that takes its cue from the classic short story "The Monkey's Paw". The slasher film Black Christmas (1974) was one of his most successful films in this period, and is remembered today as an influential precursor to the modern slasher film genre. Clark had moved to Canada, then a tax haven for Americans, and these productions were small by Hollywood standards but made Clark a big fish in the small pond of the Canadian film industry of that era.

Clark returned to his B-movie roots, though, co-writing, producing, and directing Porky's, a longtime personal project. Clark had a detailed outline based on his own youth in Florida, which he dictated into a cassette recorder due to illness, and collaborator Roger Swaybill said of listening to the tapes, "I became convinced that I was sharing in the birth of a major moment in movie history. It was the funniest film story I had ever heard." Though set in the United States, the film would go on to gross more than any other English-language Canadian film. The film was the third most successful release of 1982 and by the end of the film's lengthy initial release, in 1983, Porky's had secured itself a spot, albeit short-lived, as one of the top-25 highest-grossing films of all time in the US. The film was (also briefly) the most successful comedy in film history. Porky's overwhelming success is credited as launching the genre of the teen sex comedy so prevalent throughout the 1980s and which continued into the millennium in such movies as the American Pie films. Clark wrote, produced, and directed the film's first sequel, Porky's II: The Next Day (1983), which shifted the focus away from the title character to two new antagonists with perhaps greater relevance, a sleazy local Politician who cynically caters to the influence of a blustering fundamentalist preacher while seducing a teenage girl. Clark refused involvement with a third film, Porky's Revenge!, which brought Porky and the sexual exploits of the cast back front and center as in the first installment.

He instead collaborated with Jean Shepherd on A Christmas Story, which critic Leonard Maltin described as "one of those rare movies you can say is perfect in every way". Although not a box-office smash in its theatrical release, A Christmas Story would go on to become a perennial holiday favorite via repeated TV airings and home video. A joint effort at a sequel in 1994, My Summer Story, did not fare as well; Maltin said that the studio waited too long, and Clark was forced to recast almost the entire film. Three other film versions of the Parker family had been produced for television by PBS with Shepherd's involvement during the late 1980s, also with a different cast, but without Clark's participation.

Clark executive-produced the moonshine movie Moonrunners, which was used as source material for the TV series The Dukes of Hazzard. Clark later produced the 2000 TV movie The Dukes of Hazzard: Hazzard in Hollywood. Clark and others sued Warner Bros. over the studio's 2005 movie The Dukes of Hazzard, winning a $17.5 million settlement just prior to the movie's release.

Clark and his son, Ariel Hanrath-Clark, 22, were killed in a head-on car crash on the Pacific Coast Highway in Pacific Palisades, Los Angeles on the morning of April 4, 2007. The crash occurred when an SUV crossed the median and struck Clark's Infiniti I30, causing the closure of the highway for eight hours. Police determined that the SUV's driver, multi-deported illegal immigrant Hector Velazquez-Nava, had a blood alcohol level of three times the legal limit and was driving without a license. He initially pleaded not guilty to two counts of gross vehicular manslaughter, but changed his plea to no contest in August. On October 12, 2007, Velasquez-Nava was sentenced to six years in prison under the terms of a plea agreement.