The gang go to visit Daphne's friend, Lisa, for her birthday, which is at a very old hotel on an island that Lisa would inherit on the day after her eighteenth birthday. Velma says that it is believed that there are vampires on the island, but she herself thinks it is nonsense. But when a real vampire shows up and Lisa is turned into a vampire herself, the vampire legend becomes very believable.
The gang, along with Scooby Dum, heads to Great Skull Island to meet Daphne's friend Lisa, who is about to inherit her family's hotel. Before they arrive, Velma notes that Skull Island is rumored to be home to vampires. As soon as they arrive, the ferry captain asked them to take a box to the hotel for one of the guests. As Shaggy and Fred carry it, they drop it, revealing the package to be a coffin. Scooby Dum opens it and a bat flies out.
They arrive at the hotel, and give the coffin to Mr. Dracul, who needed it for an undertaker's convention. They meet Lisa and her uncle, Leon, and decide to turn in for the night. While they sleep, Daphne awakens and sees a vampire standing in front of her bed. She calls for help and everyone arrives causing the vampire to flee. They begin searching for clues, when Scooby Dum discovers a ventilating duct, explaining how the vampire got into the room. Shaggy, Scooby, and Dum crawl inside to search, while Fred, Velma and Daphne tell Lisa what has been going on. The phone then rings, and Daphne answers it, hearing only a high pitched bell. Meanwhile, Shaggy, Scooby and Dum search the room, and the vampire then appears and begins to chase them.
After escaping, the gang reunites and discover a dog whistle on the floor, a clue. Uncle Leon then arrives and reveals to Lisa that her grandfather was actually a vampire, who was determined to turn Lisa into one. The gang begins to split up and look for clues. Shaggy, Scooby and Dum stay to guard Lisa, who answers the phone, hears the high pitched bell, and turns into a vampire. She begins to chase them along with the vampire, who Shaggy has now dubbed "Gramp the Vamp". They escape and find Fred, Velma and Daphne, who have found a paper titled "Exo 6 Desmo". Shaggy and the Scoobies then see Gramp the Vamp lead Lisa into a coffin. They inform Fred and the girls about the situation and Velma smacks Lisa's face a few times. This causes Lisa to wake up, and she doesn't remember what happened after the bell rang.
They then devise a scheme to trap Gramp the Vamp. They succeed (but not in the way they intended), and the vampire turns out to be Uncle Leon. His motive was to get the inheritance of the hotel away from Lisa. He invented the story of Lisa's grandfather being a vampire, and somehow unknowingly hypnotized her, with the bell being a post-hypnotic trigger that would make her think she was a vampire. That way, she would be put away and would give him the hotel. The paper found by the gang was an order from Uncle Leon to "Exo", the local exotic petshop on the mainland, for 6 "desmo", vampire bats (whose Latin family name is Desmodontidae). He used the silent whistle to call the bats.
After Fred says, "Next stop: Lisa's hotel!", the Mystery Machine's driving animation is more smooth, and the vampire materializes from its exhaust using a spacey sound. (In the original, the Mystery Machine had more crude animation, and the camera zoomed out to show the vampire.)
Some more sound was added, especially to Scooby-Dum's reactions as he and Scooby-Doo try to load the coffin into the Mystery Machine.
Mr. Dracul has a softer voice.
When Shaggy and Dracul carry the coffin, the transition from light to dark is rougher.
The scene where Shaggy and the Scoobies are blocking the door from the vampire (as Lisa gets her post-hypnotic trigger phone call) is flipped so that the door is on the left.
When the Scoobies trap the vampire in the coffin, he doesn't keep bobbing up and down after he sinks.
Vampire bats are found only in South America, and cannot be domesticated nor sold as pets (at least not legally).
Fred calls Scooby-Doo and Scooby-Dum brothers, saying to Shaggy "you and the Scooby brothers stay and guard Lisa".
When Lisa turns into a vampire and Scooby-Dum sees her, Shaggy and Scooby are pushing the bed to the left, but then when Scooby-Dum runs to them, they are seen on the right.
The two moments Lisa turns into a vampire (in the present and flashback) are different:
Present: When Lisa picks up the phone, she hears the bell ring and when she hangs up the phone, she is already seen as a vampire with a scary face and vampire teeth.
Flashback: When Lisa picks up the phone, she hears the bell ring and when she hangs up the phone, her face is still normal, then she opens a drawer, takes out a pair of vampire teeth and puts them in her mouth, to which we then see a close-up of Lisa and right after the close-up comes and Lisa puts the teeth in, it's there that her face becomes scary.