Two years after a fallout during one of their mysteries, the members of Mystery Inc. have gone their separate ways, pursuing solo careers. Fred is now a celebrity, Daphne tries to prove she can fend for herself, Velma continues her intellectual pursuits, and Shaggy and Scooby-Doo enjoy an easy-going life. Their paths cross once again when each receives an invitation to Spooky Island, a popular resort owned by Emile Mondavarious, who claims that the visitors to the island are behaving strangely after returning home. Sensing the opportunity for a reunion and a chance to solve a real mystery, the gang reluctantly decides to team up once more and head to the island.

Upon arrival, they discover that the tourists are transforming into mindless drones. While investigating, the gang encounters an array of spooky characters and creatures that lead them to uncover a complex plot that threatens the fate of the island. Their investigation reveals that there is much more at stake than just the sanity of the tourists, as they face their personal challenges and the dynamics within the group. With their unique skills and quirky methods, they must navigate through the mystery, deal with their interpersonal issues, and work together to solve the mystery before it's too late.