While explosively stripping the evil pirate LeChuck of his demonic mojo, Guybrush Threepwood inadvertently infects the entire Caribbean with the arch-fiend's expelled voodoo, which threatens to transform buccaneers into unruly pirate monsters. Pursued by a notorious cut-throat Pirate Hunter and a creepy French Physician who believes that Guybrush's eerily-infected hand holds the secret of eternal life, Threepwood sails the seven seas in search of La Esponja Grande, a legendary sea sponge with unparalleled voodoo exfoliating abilities. But little does Guybrush know, his quest is part of a larger, more sinister plot, and good and evil are not always as they seem.