Ms. Bitters is the teacher of Zim's and Dib's class at Skool. A tall, slender old woman of unknown age or origin, she's a grumpy hag who is devoid of any positive emotion and full of demonic hatred for the sun, children, and life in general. Her first name, if she even has one, is unknown. Ms. Bitters was voiced by the late Lucille Bliss. In the Spanish dub, she was voiced by the late Rosanelda Aguirre.

Directly pulled from Jhonen Vasquez's earlier comic book series Squee! (where she was the title character's unnamed teacher), she evidently possesses paranormal powers, including the ability to materialize out of shadows, levitate, and adopt snake-like movements. The biography on the back of the Nickelodeon electronic trading card (written by Eric Trueheart) states that Ms. Bitters isn't human and that she did not come to work at the Skool, but rather, was always there and the Skool was built around her. In "Career Day", however, she stated that she had once wanted to be an astronaut. Another strange factor is a scene during the Halloween Spectacular of Spooky Doomin which Ms. Bitters is shown in a flashback as having once been a fairy princess before flying straight into a bug zapper. Her exact origin was later questioned by her students in Issue 15of the Invader Zim comic series during her absence. Although many of the children's theories seemed plausible, the most likely was Gretchen's. She believed that Ms. Bitters was an extremely intelligent insect queen who spread a message to her servants to study human strengths and weaknesses. They pursued the second part of Ms. Bitters' plan and started a war with the Humans. They lost a lot of bugs, but still gained the upper hand and the humans retreated. Ms. Bitters and her bugs, now low in numbers, burrowed under the Skool, and now they wait patiently in hiding for the right time to strike again. If Ms. Bitters was an insect queen, this would explain her odd tendency to be covered in cockroaches, her prolonged immunity of lice, and the insect-like appearance of Nightmare Bitters, who also happened to be the leader of all the other doppelgängers. A Ms. Bitters bug was also spotted by Poonchy, smirking at him menacingly as he watched in horror and awe.

In some early episodes, she appeared to be covered in cockroaches. When her students displease her, she habitually looms over them or bends freakishly with her twisting, serpentine length, clawed hands, and bared teeth while emitting a low-pitched, bubbling growl, feeding the possibility that she is inhuman. Details on her history are unknown.

Whatever she is, it has been suggested that she cannot survive in direct sunlight, as seen in "The Voting of the Doomed". In this same episode, she was wearing a black, hooded cloak like a vampire, thought to protect her from the sun. She greatly dislikes children, and has expressed frustration at school overcrowding, as well as disdain for traditional holidays such as Halloween and Valentine's Day (although dislike for the latter could be justified, considering an unknown event in the past changed Valentine's Day tradition from giving out chocolate and cards to giving "Valentine meat slabs"). In the "Halloween Spectacular of Spooky Doom", Ms. Bitters was revealed to have an even more demonic and humorous doppelgänger in an alternate dimension: a Satanic creature known as Nightmare Bitters, who is the ruler of that dimension.

Since Ms. Bitters is one of the most petulant teachers in the skool, she often horrifies her students with grotesque "recollections": she claimed to have once been a fairy princess until she was shocked with a bug zapper in "Halloween Spectacular of Spooky Doom", and in "Career Day" and the Original Pilot she claimed to have been an astronaut until her spaceship imploded. She also has a dark disposition, which she puts to good use in her "lessons". In "A Room with a Moose", one of said "lessons" was to memorize the copyright information of one of the textbooks, and she stated there would be a quiz on it. She was similarly horrific and inept at teaching in Squee!, as she taught the class that Christopher Columbus discovered America in 1429 instead of 1492, even screaming "DESTROY THE NONBELIEVER!" when Squee corrected her, turning his classmates into "textbook zombies".

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