The character of Jerri is based on motivational speaker Florrie Fisher, who travelled high schools in the 1970s talking about her fall from 1940s socialite to a heroin addicted prostitute in the 1960s. Many lines of dialogue in the show are taken verbatim from a recording of a speech she gave to a New York high school, which circulated for many years on the cult video market as "The Trip Back". In real-life, Fisher fell out of the public eye in the early 1970s, and for many years was believed to be missing and presumed dead. In the late 2000s, researchers turned up an interview with Mike Douglas in a 1973 issue of the Rotary Club publication "The Rotarian", in which Douglas recounted interviewing Fisher. According to Douglas, Fisher's disappearance was due to her being taken to a Miami hospital in the middle of her lecture tour, where she was diagnosed with liver cancer. The disease resulted in kidney failure, and she ultimately died of a heart attack on May 26, 1972 at the age of fifty-four.

The characters Jerri Blank and Principal Blackman received their names from the script, but in a uncommon fashion. The script notes described the principal as a black man, and the writers had not yet come up with a last name for Jerri, so they left a blank ("Jerri _______"). These descriptions struck the writers as fitting, so they were used in production for the characters' actual names.

A running gag throughout the series is that a different artistic representation (painting, sculpture, et cetera) of Principal Blackman appears in each episode.

The first and second seasons were filmed in an abandoned elementary school, which included a bizarre padded room that looked like it belonged in an insane asylum. This room inspired the writers to introduce the element of the violent students in the episode "Bogie Nights", which features a Violent Students Lounge. There was very little set dressing necessary for that particular scene.

Amy Sedaris still worked as a waitress at Mary's Fish Camp during the show because she enjoyed having a real job. She considered observing customer interactions as character study and especially enjoyed when they got angry. She eventually had to quit because fans would recognize her from the show and ask to sit in her section.

Greg Hollimon made his film debut in The Fugitive (1993) as the "Skating Orderly". In both "The Trip Back" and "Ask Jerry", Hollimon's character Principal Blackman shows off his roller skating prowess.

Sarah Thyre (Coach Wolf) was originally casted to play Sara Blank. But the part later went to Deborah Rush.

Jerri's father Guy was killed off in the second season when creators ran out of ideas for the running gag of Guy never moving on-camera. They described Guy as going from the easiest character to write for to the hardest one.