Escape from Monkey Island finds Guybrush Threepwood and his new bride, Governor Elaine Marley-Threepwood, returning to Melee Island? from their honeymoon. They quickly discover Elaine has been declared dead, the Governor's mansion is scheduled for demolition, and the slick, yet hauntingly familiar politician, Charles L. Charles, is gunning for her job.

While Elaine scrambles to launch a reelection campaign, Guybrush is dispatched on a seemingly trivial legal errand that catapults him into a maelstrom of thievery, voodoo, and experimental prosthetic devices. Armed only with his sharp wit and an uncanny ability to hold his breath for ten whole minutes, our hero navigates ever deeper into a villainous scheme to wipe out the Tri-Island Area using the fearsome power of the Ultimate Insult. Can Guybrush make the Caribbean safe for fun-loving, grog-swilling pirates, or will the twin forces of heckfire and unbridled capitalism bring an end to the swashbuckling merriment?