The main villain, Dr. Pretorius (voiced by Tim Curry), was a madman who had his own head removed from his body and placed on tiny, spider-like robotic legs, which could attach to a larger android body. His plans always revolved around either obtaining or controlling the Mask (Pretorius is one of the few characters in the series aware of The Mask's true identity), or as part of some increasingly insane "science experiments" which, if carried out, would result in the death of thousands or even the end of mankind. He mostly pronounces Ipkiss' last name as "Ipp-kiss". Pretorius was also likely a parody of drug dealer/mob boss Eugene Rapaz from the original comics (both share the same face. Rapaz wore small, rounded-lens dark glasses and Pretorius had round optic implants that looked similar, as well).
In the episode, "Sister Mask", Dr. Pretorius did eventually gain the mask, and as with Tyrell, retained his own personality while wearing it (While the mask is said to release one's own inhibitions, those who have no inhibitions seem to retain full conscious control while wearing the Mask, such as the Joker in the DC crossover).
Coming from the comics was Walter, Pretorius's goon, still silent and indestructible but not as murderous and cruel. Walter chased the Mask for several episodes, but when he obtained the wooden mask and it failed to work for him, he simply dropped it. Walter remained a recurring character throughout the series. He is strong enough to actually break the Mask in two (an impressive feat as only seconds before the Mask withstood being hit by cars and run over by a steamroller without a scratch).
Ben Stein reprised his role as Dr. Neuman, from the movie. In one episode, the mask falls into Neuman's hands, and he becomes a super-villain. Dr. Neuman rampaged throughout the city, claming everyone suffered from a disease he called"Ipkissiamascosus". He was determined to kill Stanley and even goes as far as to spring Pretorius from prison to aid him (a running gag, however, was that Dr. Neuman refused to believe the mask worked, even when he had it on).
A third villain who made it to the TV series for a few times was the mad Dr. Amelia Chronos, who, with her ambitions of gaining power and dominance through the manipulation of time, often caused quite a lot of chaos through inventions like a machine that kept looping time every half hour for everyone but herself (so that even the Mask could never foil her plans, since by the time he got to her, everything would be reset to a half hour prior), a gun that reversed/fast forwarded time for whoever it was aimed at (so that the person would keep getting younger and younger until he/she became nothing, or became older and older until he/she was dead), a large time portal through which she could summon anything to defeat the Mask (such as prehistoric creatures, robots from the future, etc.) though none of them worked and an actual time machine through which she could travel into the past or future to manipulate events so that she would ultimately be victorious in her quest for world dominance.
For villains as for the Mask's transformation, there was often DC Comics parodies, as Supermask and Super Salad Man (a parody of Superman). Some Marvel references were made too, like The Mask becoming Biclops (a parody of Cyclops), Spiderhyny (alias Spiderman), Green Surfer (alias Silver Surfer) and Toolverine (a parody of Wolverine), and a villain that turned into a dinosaur like Sauron. Notable were Skillit (parody of Mr. Mxyzptlk and Peter Pan, albeit much more malevolent in nature) and Putty Thing (parody of the version of Clayface, portrayed as a dumb teenager rather than an angry, jaded actor).
The Mask also had a few more villainous enemies in his rogues gallery such as:
Stanley Ipkiss is the owner and wearer of The Mask, but there have been others who have worn the Mask (either accidentally or intenionally). Some episodes focus on this aspect; someone gets his/hers hands (or face) on the Mask and Stanley usually tries get it back with difficulty. The other wearers are:
1 & 2. The Mask Is Always Greener on the Other Side (Parts 1 & 2): After causing him nothing but trouble, Stanley Ipkiss gets rid of his mask by burying it in quick-drying cement, but must retrieve it to save Peggy and Milo after Pretorius tricks Stanley's friend and coworker, Charlie, into building a "house of tomorrow" and kidnaps them.<br>
3. The Terrible Twos: When Kellaway tries to prove that Stanley is the Mask by handcuffing the two together, Stanley must go to elaborate lengths to get away from the detective when two mutants Putty Thing and Fish Guy (formerly two teenage slackers named Dak and Eddie who irradiated themselves so they can become superheroes) go on the rampage.<br>
4. Baby's Wild Ride: A baby-sitting job turns difficult when the infant acquires the Mask and joins a biker gang with their chief Lonnie The Shark (who is posing as children's show host Barnaby the Dinosaur).<br>
5. Shadow of a Skillit: The youth-stealing Skillit has come to Edge City to steal the souls of Charlie, Peggy, and Milo, and only the Mask can stop him.<br>
6. Sister Mask: Pretorius creates a sister Mask that turns the real Mask into a living puppet in order to use him to steal meteorite fragments with unusual properties.<br>
7. Bride of Pretorius: Stanley dates a shy, quiet girl who works at her bank—and becomes a loud, man-hungry woman when she stumbles upon The Mask. Meanwhile, Pretorious looks for a female companion.<br>
8. Double Reverse: A reverse therapy treatment helps Stanley deprive the Mask of its power by acting like the Mask in his normal state, but when a criminal called Kablamus, capable of exploding and surviving, arrives in the city, Stanley must get the powerless Mask to work once again.<br>
9. Shrink Rap: Stanley rids himself of the mask by giving it to his therapist, Dr. Neuman, who puts it on and starts going on a rampage and joins up with Pretorius, who's planning to nuke the city so he can use the flash of the explosion to photograph an alien race's planet.<br>
10. Martian Mask: FBI agents mistakenly believe The Mask is actually an alien bent on world domination and do everything to capture him, whilst Putty Thing and Fish Guy go on a road trip.<br>
11. Mayor Mask: Frustrated by Edge City's mismanagement, Stanley puts on the Mask hoping he will teach Mayor Tilton a lesson. Instead, The Mask announces his candidacy against Mayor Tilton as the new mayor of Edge City. Though Stanley naturally objects, he is then forced to make sure his alter ego wins the election when he discovers the real Mayor Tilton was captured and that Dr. Pretorius is masquerading as him so he can turn all of Edge City into subjects for toxic waste experiments.<br>
12. How Much Is That Dog in the Tin Can?: Milo puts on The Mask to battle an insane dogcatcher capturing dogs for a (somewhat) sinister purpose. Meanwhile, Walter starts stalking Stanley.<br>
13. All Hallow's Eve: On Halloween night, Skillit escapes from reform school, determined to get revenge on the Mask for making him do homework.<br>
14. Santa Mask: All the villains in Edge City begin disguising themselves as Santa Claus and committing crimes. The Mask must save Christmas by proving Santa's innocence.<br>
15. Split Personality: The Mask breaks in half, resulting in both Stanley and the Mask existing at the same time; unfortunately, with Walter after the Mask and an old high school acquaintance of Stanley's after revenge on Stanley for getting him expelled, the two personalities must work together to piece the mask together.
16. A Comedy of Eras: The Mask battles a mad female scientist named Chronos who sends The Mask to the future and to the era of the Salem Witch Trials.<br>