A brother and sister along with their sarcastic talking cat move into a mysterious mansion in Blackburrow, North Dakota, being filled with supernatural beings and new friends.
- Franklin "Frank" Woodson (voiced by Greg Cipes) - a shy teenager who discovers the mysteries of Mystery Manor while he deals with his normal life.
- Emily "Emma" Woodson (voiced by Ashley Johnson) - Frank's older sister who is intelligent and cares for animals, helping her brother to find out the mysteries of Mystery Manor.
- Tyler the Cat (voiced by Charlie Adler) - a sarcastic talking cat who is Emma's pet, often getting in trouble due to his nature and his tendencies to cause problems.
- Professor Bram Woodson (voiced by Liam O'Brien) - a mysterious man who is Tyler and Emma's uncle and their TBD.
- Tiffany Van Holde (voiced by Kath Soucie) - the tough maid in Mystery Manor who TBD.
- The Friendly Banshee (voiced by Rob Paulsen) - a friendly banshee who lives in Woodson's refrigerator.
- Alexis "Alex" LeStorm (voiced by Elizabeth Daily) - a bully who likes to torment Frank and Emma, often calling them nerds.
- Julia Juneson (voiced by Grey Griffin) - a nerdish girl who gains a crush on Frank and later begins helping him and Emma to solve mysteries and fight the supernatural.
- Theodore "Teddy" Blake (voiced by Will Friedle) - a cool teenager who loves being cool, being attracted to Emma and tries his best to win her attention.
- Mayor Vanessa McCreep (voiced by Cristina Pucelli) - the mayor of Blackburrow who is known for her creepy nature.
- Chief Adrian Cruise (voiced by Steven Blum) - the head of the Blackburrow Police Department who is very serious.
- Kri-Sten/Kristen Willis (voiced by Kari Wahlgren) - a beautiful and intelligent tribal teenage girl who felt in love with Frank and wants him to be her mate for life as she believes that he is the reincarnation of an ancient warrior.
- Harry the Gnome (voiced by Jim Cummings) - a magical gnome who lives in the Manor's gardens.
- Bella the Light Witch (voiced by Kristin Chenoweth) - an ancient witch who believes in hope and peace.
- Ghosty (voiced by Jeff Bennett) - a prankster ghost who loves causing pranks.
- The Cupid (voiced by Tara Strong) - a cupid who is a moron.
- The Shadow in the Red Curtains (voiced by Laura Bailey) - a shadow person who was trapped inside the red curtains.
- The Fright Maiden (also voiced by Kath Soucie) - TBD
- Dr. Mad Stitches (voiced by Keith David) - a mad scientist who seemly lives in the basement of the Mystery Manor.
- Madame Banshee (voiced by Jennifer Hale) - a banshee who hates mankind.
- The Black Queen (voiced by Andrea Baker) - a young, wicked and immortal queen.
- The Black Knight (voiced by Greg Baldwin) - an immortal knight who serves the Black Queen.
- The Dragon (voiced by Khary Payton) - a vile and dangerous red dragon who is locked in the dungeon.
- Rodagog (voiced by Mark Hamill) - a orc who loves treasure and usually destroys anything that he wants to.
- Maria the Dark Witch (voiced by Kaley Cuoco) - Bella's cruel sister who believes in the exact opposite taking pleasure in chaos and hate.
- Mr. Conwell (voiced by Eric Bauza) - a mysterious con-man who sells fake items to gain cash, often serving as an annoyance to Woodson.
- The Chimera (vocal effects by Frank Welker) - a creature with numerous body parts who tries to eat anyone.
- Ba-King (voiced by S. Scott Bullock) - the sadistic chief of the Noctis Tribe and Kri-Sten's father who wanted to sacrifice Professor Woodson due to believing that he's actually an ancient being who wants to corrupt Emma, since she's mistaken by the tribe as a powerful goddess.
- Love Sucker (voiced by Tom Kane) - a strange creature who turns people into loveless creatures.
- The Krampus (voiced by Bumper Robinson) - TBD
- Stephanie (voiced by Liliana Mumy) - a spider-like monster who disguises herself as a teenage girl to get victims to eat.
- Slithery Sam (voiced by John Michael Higgins) - a snake-like creature who allowed venomous snakes to infest the manor.
- The Demon Bird (vocal effects by Dee Bradley Baker) - a vulture-like bird that is a demon. When Emma found him, he kept him as a second pet, but whenever she's not around, it tries to eat Frank and Tyler.
- The Scarecrow (voiced by Lex Lang) - a scarecrow who TBD.
- Truth (voiced by David Kaye) - a powerful being who forces people TBD.
- Bram (voiced by Seth Green) - a vampire who kidnapped Emma to make her the vampires' queen.
- The Superpunch Gals, consisting of:
- Arthur Beast and James Weinerman (voiced by Adam Savage and Jamie Hyneman, respectively) - two famous monster hunters who were Frank's idols until they show their true selves when it turns out that they TBD.
- Harris Christianson (voiced by John Paul Karliak) - TBD
- The Erebos Family, consisting of:
- TBD Erebos (voiced by TBD) - TBD
- Chica and Lincoln (voiced by TBD and TBD, respectively) - a couple of burglars who like to steal things from houses for the fun of it.
- Bionic Marsha (voiced by TBD) - TBD
- The Shapeshifter (voiced by TBD) - TBD
- Screw Ball (vocal effects by TBD) - TBD
Although most of the series' episodes have no connection to each other, events from previous episodes are commonly mentioned in further episodes and the series has presented some occasional story arcs as well.
- Light and Dark (Season 1, Eps. 25-26)
- Night Island Adventures (Season 3, Eps. 1-10)
- Catch the Demons (Season 3, Eps. 23-26)
- The Crossing (Season 5, Eps. 13-16)
See Night Island.
A 13-episode miniseries based on the Night Island arc was eventually produced in August of 2018, focusing on Kri-Sten and involves her adventures in the Night Island before the arrival of the Woodsons.
When the show first premiered on Cartoon Network, it was met with mixed reviews. While it was praised for the animation, writing and humor, some criticized it because they thought it would be too similar to Gravity Falls, mainly due to the concept of a brother and sister staying at a weird place.
However, as the show progressed, reviews of the show were more positive.
- Spanish: Los Misterios Misteriosos de la Mansión del Misterio
- French: Les Mystères Mystérieux du Maison de Mystère
- Italian: I Misteri Misteriosi della Dimora del Mystero
- Portuguese: Os Mistérios Misteriosos da Mansão do Mistério
- German: Die Geheimnisvollen Geheimnisse des Geheimnis Villa
- Russian: Загадочные тайны загадочного дома
- Japanese: ミステリーマナーの謎の謎
- Korean: 의 신비로운 신비의 미스터리 매너
- Greek: Τα μυστηριώδη μυστήρια του Μυστήριο Αρχοντικό
- Cantonese: 神秘庄园的神秘之谜
- Norwegian: Den Mystiske Mysterier av Mystikk Manor
- Finnish: Mysteerikartanon mysteerit
- Swedish: Mysteriet Herrgård
- Polish: Tajemnicze Sekrety Tajemniczego Domu
The animation for the series is outsourced to Rough Draft Studios in Seoul, South Korea.
- According to the series, Frank is 16, Emma is 20, Tyler is 3 (28 in cat years), Professor Woodson is 42 and Tiffany is 36.
- Despite being originally an one-shot character in the Night Island miniseries, Kri-Sten became instantly popular due to her attractive appearance and her will, leading to the production crew adding more appearances in further episodes, becoming a breakout character.
- Since TMMoMM had six crossover specials, this makes this the show with the most crossovers on Cartoon Network, beating OK K.O., which had five crossover episodes.
- The show, by far, has the longest title out of every other Cartoon Network show.
- Cartoon Network Studios: The custom animation is Frank, Emma and Tyler shoving a paranormal arm down a closet, then sighing in relief after successfully locking it out.
- In TBD, Professor Woodson mentions a giant pink demon, referring to Him.
- In TBD, Tyler finds a purse belonging to Dee Dee.
- In Emma's Second Pet, Emma, at one scene, compared Frank and Tyler to Courage.