Clawdeen Wolf is a half-werewolf half-human biracial girl, born from a human father, named Apollo, and werewolf mother, named Selena (who passed away for unknown reasons). Due to being part monster, Clawdeen spent her whole life in the world of humans hiding from people. On Clawdeen's 15th birthday, she receives an invitation to study at Monster High, a high school for monsters her mother used to attend. Although reluctant, Apollo agrees to let her attend the school. He warns her that she must hide her human side, because humans are considered monsters' biggest threat and only "true monster hearts" are allowed in the school.

Upon arriving at Monster High (which is depicted as a boarding school), Clawdeen finally feels like she belongs somewhere. She befriends Frankie Stein, a non-binary Frankenmonster who is just 15 days old with a brilliant brain made from different brain bits, and falls in love with Deuce Gorgon, son of Medusa and Lyra. She also meets Draculaura, daughter of Dracula who is pressured by her father to be a top student, Cleo de Nile, daughter of the Mummy, the school's Queen Bee and Deuce's ex-girlfriend, Lagoona Blue, Colombian daughter of a Sea Monster and a Sea Nymph and Cleo's best friend, and the Zombie Ghoulia Yelps who helps her find her dormitory. The school's Headmistress Bloodgood invites Clawdeen to speak at a dinner with the Monster High Council on Founder’s Day to represent the students, to which she agrees.

During her time at Monster High, Clawdeen discovers that she temporarily transforms into a full human when she feels strong emotions like fear or nervousness. During her first class, her new professor, Mr. Komos, teaches the students about the history of Monster High and how humans are hated by monsters. He tells them the story of Edward "Eddy" Hyde, a half-human half-monster former student who was expelled from the school when his human side was discovered and was killed by human hunters, which makes Clawdeen fear getting discovered even more. She learns from Mr. Komos that Hyde created a formula that could transform a half-human half-monster into a full-blooded monster, but he never tested it due to being expelled before he could. Clawdeen decides to find and drink the formula so no one will find out her secret and researches Hyde.