In the film, Dracula is considering retirement and plans to hand over control of his beloved hotel to his daughter Mavis and her human husband, Johnny. However, Drac has second thoughts, secretly worried that Johnny's human lack of subtlety will ruin the legacy he has built. To prevent this, Drac lies about a hotel law that prevents Johnny from owning the establishment since he is not a monster. Desperate to fit in, Johnny turns to Van Helsing, who uses a mysterious crystal device to transform Johnny into a fiery monster. Meanwhile, the device accidentally changes Drac and his monster friends into humans, stripping them of their powers and appearances they have always known.

Now unexpectedly trapped in a human body, Drac must navigate the new challenges and limitations with Johnny by his side. The duo sets off on a journey across South America to find a remedy before the transformations become permanent. Their quest is riddled with obstacles, eccentric encounters, and quirky adventures, pushing them to confront fears and prejudices. As Mavis and the gang rally to track down Drac and Johnny, there is an innate urgency to reverse the changes. Along this transformative journey, everyone discovers new perspectives on acceptance, embracing differences, and what it truly means to be a family. The journey unravels surprising dynamics and tests friendships as they race against time to return to their original forms.