The story alternates between two protagonists, Melody Carver and Frankie Stein, as their lives converge at a high school in Salem, Oregon, where families of hidden monsters live among ordinary humans.
In a brief prologue, scientist Viktor Stein and his wife, Viveka, bring their daughter Frankie to life in their laboratory. Viktor has built her from artificial body parts and loaded her brain with information. As Frankie's battery drains before she can open her eyes, Viveka weeps that Frankie will have to live in hiding, just as they do.
The narrative shifts to Melody Carver, a 15-year-old whose family is relocating from Beverly Hills to Salem. Her father, Beau, is a plastic surgeon, and her older sister, Candace, is conventionally gorgeous. Melody was the genetic outlier, once having a bumpy nose and fanglike teeth. Severe asthma stole her singing voice at eight. Beau performed rhinoplasty under the pretense of treating her breathing, giving her a new nose and veneers. Melody was accepted for the first time but felt hollow, knowing it was only because of her new face. After a severe asthma attack, the family moved to Oregon for cleaner air.
Meanwhile, Frankie, now 15 days old and fully developed, lives in her father's laboratory. Viktor and Viveka reveal that her skin is green, her limbs are stitched together, and bolts on her neck allow her to recharge. They show her their own hidden green skin, covered daily by stage makeup, and explain that their family descends from what ordinary humans, or "normies," call monsters. They prefer the term RADs, or Regular Attribute Dodgers. RADs once lived openly until horror films of the 1920s and '30s portrayed them as evil. The RADs fled to Salem, built a hidden community on Radcliffe Way, and have lived in disguise since. Frankie must cover every trace of her true self before attending Merston High.
In Salem, Melody and Candace settle into a log cabin on Radcliffe Way. At the Riverfront, Melody meets Jackson Jekyll, a boy from across the street. Jackson writes his phone number on a sketch, but a smudge renders a digit illegible, so Melody's calls never reach him.
Frankie, refusing to wear makeup, is driven by Viktor to what she believes is Merston High. It turns out to be the wrong school on the wrong day. Cheerleaders see her green skin and seams and call 911. Viktor speeds her away. Devastated, Frankie agrees to wear her disguise at the real school.
On the first day, Melody clashes with Cleo, a domineering classmate with Egyptian features, over a minor collision. Cleo retaliates by grabbing Jackson and kissing him publicly. Jackson reciprocates and acts nothing like himself, snapping his fingers and dancing. Melody is humiliated. Bekka Madden, who despises Cleo, offers Melody friendship in exchange for a signed contract promising never to flirt with Bekka's boyfriend, Brett Redding. Melody signs.
Frankie starts at Merston concealed under makeup and a scarf. In class, a bold classmate named D.J. dubs her "Firecracker" after she shocks him with static. She befriends Lala, a Goth girl, and Blue, a dry-skinned Australian who wears gloves. She develops a crush on Brett, whose Frankenstein T-shirt makes her believe he might accept her true self.
By week's end, Cleo drops Jackson for her actual boyfriend, Deuce, who has returned from Greece. Bekka goads Melody into kissing Deuce publicly to retaliate. Afterward, Melody finds a smashed ceramic bouquet; one petal reads "FOR MELODY," revealing Jackson had been bringing her flowers.
During a spa trip with her RAD friends, a tanning bed overcharges Frankie's body, causing her seams to smoke and bolts to spark. A surge of electricity blacks out the facility, and Frankie flees. That Saturday night, Jackson appears at Melody's house, claiming he has blackouts and does not remember kissing Cleo. He discovers her old school ID and tells her she looks "the exact same." He asks her to the September Semi dance, and she accepts.
Viktor and Viveka take Frankie to a secret gathering called RIP (RAD Intel Party), held beneath the Riverfront carousel. Frankie discovers her school friends are all RADs: Lala is a vampire, Blue has fins and webbed digits, Cleo is a mummy, Clawdeen is a werewolf, and Deuce is a Gorgon with snakes for hair. Ms. J, Jackson's normie mother, leads the youth group, and Lala reveals that Ms. J's son is a RAD who does not know it. When the dance theme is announced as "Monster Mash," Frankie proposes the RADs attend as themselves. The group votes 43 to 2 against her; only an invisible boy named Billy privately sides with her.
Melody and Jackson grow closer, sharing their first kiss during a film shoot behind Jackson's house. The prolonged heat under a thermal blanket triggers Jackson's transformation: He no longer recognizes Melody and mentions someone called "Firecracker." Later, Jackson overheats at Melody's house and transforms before her and Candace, calling himself D.J. Hyde. When the room cools, Jackson returns with no memory. Melody shows him her video of the transformation, and he flees. She follows and eavesdrops as Ms. J reveals the truth: Jackson's great-grandfather was Dr. Jekyll, whose potion corrupted his DNA. In Jackson, overheating triggers D.J., a confident alter ego.
Viktor forbids Frankie from attending the dance. Undeterred, Frankie texts her RAD friends that Melody will attend with Deuce, provoking Cleo's jealousy, and persuades the group to appear as themselves. Frankie dons the original Bride of Frankenstein gown from her family's garage and escapes through her window.
At the dance, Jackson reconciles with Melody, revealing he left his front door open deliberately so she could learn his secret voluntarily. They dance, Jackson staying cool with a mini-fan. The RADs arrive in their natural forms, and normies compliment them, believing they wear costumes. Brett approaches Frankie, and they share a passionate kiss. Brett grips her neck and inadvertently tears her stitches, ripping her head from her body. The gym erupts in chaos. Billy grabs Frankie's head while Clawdeen's brother Claude secures her body. Bekka directs arriving police. Someone rearranges the school marquee to read "MONSTER HIGH."
Bekka orders Melody to find the monster. Jackson begs Melody to leave before stress overheats him, and D.J. emerges. Candace drives Melody home and asks what Melody would do if she were not afraid.
Viktor restitches Frankie while RAD parents blame the Steins and demand they leave Salem. That night, D.J. appears in Frankie's room and dances with her. When the room cools, Jackson re-emerges, does not recognize Frankie, and flees.
Bekka's assistant, Haylee, finds the transformation video on Melody's phone, and Bekka issues an ultimatum: Melody has 48 hours to deliver the green-skinned girl, or Bekka will leak the footage publicly. Jackson reveals he knows where Frankie lives because D.J. led him there but refuses to give her up. Melody deliberately overheats Jackson, triggering D.J., and asks him to take her to Firecracker.
In the early morning hours, Melody and D.J. climb through Frankie's window. Frankie is hostile, but Melody explains Bekka's blackmail, the video, and the ticking deadline. The two girls discover common ground: Both have felt like outsiders judged on appearances, and both want a world where people are not afraid of differences. Melody extends her hand and declares she will not surrender to intimidation. Frankie takes it, and they shake on an alliance to fight for tolerance and acceptance.