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The Zombie Island of Dr. Ned begins with an introduction from Marcus Kincaid in the form of a story being told to a small child. The child interrupts him with questions, and drawings, as he tries to recite this tale. It can be speculated that Marcus is telling the story to the same person as in the introduction of Borderlands, but the child remained quiet in that earlier introduction.

Brave players who seek zombie carnage will be tasked with keeping the remaining workers of Jakobs Cove alive. Dr. Ned (who is totally not Dr. Zed in disguise) does his job a little too well, creating zombies and other abominations that now run rampant in this region. Players will have to work alongside Dr. Ned as they embark on a quest to cure the inhabitants of Jakobs Cove in this full-fledged expansion filled with new enemies, new quests and rare loot drops.