Born in Appleton, Wisconsin, Zwigoff held several jobs before making his breakthrough feature: the documentary Crumb (1994) in 1994. His previous jobs included musician, shipping clerk, printer and welfare office worker. In fact, Zwigoff traces his film career back to discovering a rare blues recording by an unknown Chicago blues musician he discovered in 1978. The experience of the two years spent researching this artist, a highly eccentric Howard Armstrong, became Zwigoff's first film project, a documentary titled "Louie Bluie" (1985) which premiered at Telluride and Sundance before its theatrical run. Zwigoff's next project became the toast of the festival circuit in 1994. A documentary on the underground comic artist Robert Crumb, "Crumb" won the Grand Jury Prize at Sundance as well as citations from the New York and Los Angeles Film Critics and the Directors Guild of America. It also became the third-highest grossing documentary of all time and was on over 150 Ten Best lists by year's end. However, along with another 1994 documentary hopeful, "Hoop Dreams" (1994), its failure to win even a nomination in the 1994 Academy Awards' Best Documentary Feature category caused an uproar that resulted in a demand to change the way the Academy voters choose the documentary feature nominees. "Crumb" chronicled Zwigoff's acquaintance of nearly two decades of Robert Crumb's life, career, the underground comic scene as well as Crumb's dysfunctional family. Even though it caused a momentary rift between the documentarian and the comic book artist, it has been reported that they have reconciled and are currently collaborating on a screenplay called "The New Girlfriend."

Even with the enormous success of "Crumb," Zwigoff refused to sell out to Hollywood. His aversion to corporate commercialism is a well-known trademark. He turned down many more commercial projects while he struggled for five years to make a feature film out of Daniel Clowes' underground comic strip "Ghost World." Released in 2001, "Ghost World" (2001) became a summer art house hit and captured Golden Globe nominations for Steve Buscemi and Thora Birch, who played the teenage protagonist Enid. "Ghost World" also brought acclaim for Zwigoff and his co-screenwriter Daniel Clowes, a nomination for Best Adapted Screenplay in the 2002 Academy Awards. "Ghost World" wound up on over 150 Ten Best lists for 2001.