Apatow was a self-described awkward, undersized child who was always picked last for school sports teams. He was deeply scarred as a youth by his parents' divorce, and his anger over their breakup would become a recurring theme in his later work. He found his niche as the host of Club Comedy, a radio show at Syosset High School, in which he interviewed established professional comedians, including Garry Shandling, Steven Wright, and Jerry Seinfeld (Seinfeld, Jerry). At age 16 he began working as a dishwasher at a comedy club and soon launched his own stand-up act.

After high-school graduation, Apatow enrolled in the screenwriting program at the University of Southern California (USC). His tenure at USC lasted only about two years, however, and he returned briefly to stand-up before becoming a joke writer for other comedians, notably Roseanne Barr. In his mid-20s Apatow worked as a producer of television programs for fellow comedians Ben Stiller and Shandling. In 1996 he rewrote the script for The Cable Guy, starring Jim Carrey, but his work for that film was uncredited. Apatow pursued but ultimately dropped a lawsuit to list his name as a screenwriter.

Apatow went on to develop two critically acclaimed television series, Freaks and Geeks and Undeclared, in 1999 and 2001 respectively. Though both shows were canceled after just one season, their young actors would become Apatow's cinematic family, reappearing in his subsequent projects. In 2005 Apatow finally achieved unqualified success when he wrote, directed, and produced the surprise hit movie The 40-Year-Old Virgin, starring Steve Carrell, an actor Apatow met while producing the 2004 film Anchorman: The Legend of Ron Burgundy.

In 2007 Apatow became one of Hollywood's leading figures in comedy entertainment with the release of two films, Knocked Up and Superbad. Like much of his previous work, the movies drew heavily on his personal youthful experiences and featured unconventional protagonists played by largely unknown, average-looking male actors. In Knocked Up a 20-something slacker is forced to grow up after impregnating a beautiful, successful woman. Superbad features a trio of teenage boys trying to seduce the girls of their dreams before they head off to college. The films' combined success resurrected the R-rated sex comedy and firmly established Apatow's reputation.

Apatow's other films include Walk Hard: The Dewey Cox Story (2007), a biopic parody that follows a musician's exaggerated struggles with divorce and drugs when he becomes famous, and Forgetting Sarah Marshall (2008), about a man who is devastated when his television star fiancée leaves him.