Scooby-Doo on Zombie Island follows Mystery Inc. as they reunite after going their separate ways, only to face a case far more terrifying than any they've encountered before. The story begins with Daphne Blake hosting a successful paranormal television show, while Fred works as her producer and cameraman. Velma runs a mystery bookstore, and Shaggy and Scooby have grown tired of chasing fake ghosts and men in masks. When Daphne decides she wants to investigate a real haunted location for a Halloween special, the old gang comes back together, hoping to finally uncover an authentic supernatural mystery.
Their search leads them to Moonscar Island, a remote Louisiana bayou plantation owned by the mysterious and elegant Lena Dupree. The island is said to be haunted by the ghost of Morgan Moonscar, a pirate who was betrayed and killed centuries ago. Intrigued by the chilling local legends and the eerie atmosphere, the gang accepts Lena's invitation to stay the night. From the moment they arrive, the island feels different from their past cases—fog blankets the swamps, strange lights flicker in the distance, and shadowy figures seem to watch their every move.
As night falls, the team begins to experience genuinely frightening events. They encounter wandering zombies rising from the marsh, unlike the usual criminals in disguises they are used to unmasking. For the first time, the monsters appear to be real. The zombies are not merely illusions or tricks; they move with eerie determination and seem connected to the island's dark past. Velma, ever the skeptic, struggles to find a logical explanation, but the mounting evidence suggests that something truly supernatural is at work.
The mystery deepens when the gang discovers that Morgan Moonscar and his pirate crew were lured to the island and slaughtered by settlers centuries ago. As they investigate further, they uncover an even more shocking truth: Lena and her companion Simone are not innocent victims but immortal cat-like creatures who drain the life force of others to maintain their youth. The zombies are actually the restless spirits of those they have sacrificed, including Moonscar's crew, cursed to rise each harvest moon.
In a tense and dramatic climax, the gang must survive the night as Lena and Simone attempt to claim them as their next victims. Shaggy and Scooby, despite their fear, play a crucial role in exposing the truth and disrupting the ritual. When the creatures' power fades, the zombies finally find peace, and the island's dark curse is broken. Unlike many previous adventures, this case leaves the gang shaken but closer than ever, having faced real supernatural evil and proven that their courage matters even when the monsters are no longer just men in masks.