Henenlotter's films were inspired by the exploitation and sexploitation films he loved, the kind which played on 42nd Street in New York City in the 1960s and 1970s. His films are low-budget and filled with gore and special effects. They are considered by many to be B-movies, but they also turn the conventions of these films upon themselves. Although many of his films are somewhat obscure, his most well-known are Basket Case, Brain Damage and Frankenhooker.

Following Basket Case 3: The Progeny, Henenlotter became deeply involved in the release slate of the specialty video releasing outfit Something Weird Video; he has also been instrumental in rescuing many low-budget sexploitation and exploitation films from being destroyed, including the camp classic The Curious Dr. Humpp (1971). Many of these works have been released under Something Weird's specialty logo "Frank Henenlotter's Sexy Shockers."

During the 16 years following BC 3, a number of Henenlotter feature projects came close to production, including "Sick in the Head," Henenlotter's first script collaboration with R.A. the Rugged Man, at one point scheduled to be produced under the aegis of Fangoria Magazine; but, coincidental with the general economic downturn, financing evaporated. Henenlotter has also noted the conflicts he had with producers over the film, who forced the filmmaker to walk after urging him to reedit his script so it would be "more like Saw." R.A. subsequently was able to find a new deal and very modest financing through his music industry contacts, so Bad Biology was conceived to be shot for an extremely low budget, for extremely limited, unrated theatrical play, and subsequent video release. Though only attendees at film festivals and special film events have had the opportunity to see the film (shot in traditional 35mm at Henenlotter's insistence) projected in a theater, Henenlotter claims the low budget, independent financing and the decision to forgo the ratings process allowed him a level of freedom he has been missing since his earliest films. Bad Biology was scheduled for video release in January 2010 by Media Blasters. Henenlotter appeared as himself in the documentary film Herschell Gordon Lewis – The Godfather of Gore and narrated the film on the 2010 FanTasia. In issue #304 Frank and comic Artist Joshua Emerick started the Basket Case comic strip for Fangoria. The three panel strip runs in each issue.

Henenlotter appeared in the 2013 documentary film Rewind This!, about the impact of VHS on the film industry and home video. He also appeared with the film's Director, Josh Johnson, when it screened at film festivals such as the Telluride Horror Show. In 2014, he directed Chasing Banksy, which was screened with a visit of Henenlotter at New York City Forbidden Planet.