In a reversal of roles, all players in Munchkin Zombies begin as zombies, and the "monsters" are the normal people trying to stop the zombie invasion (such as the Action Hero, Soccer Mom, Fireman, etc.). Unlike most Munchkin games, there are no classes or races; instead, you have a mojo: Atomic Zombie, Plague Zombie, and Voodoo Zombie. As with Munchkin Bites! and Super Munchkin, Munchkin Zombies comes with powers – special abilities that you can play as you gain levels.

The guest artist is Alex Fernandez, who drew the Meals on Wheels card.

Munchkin is a satirical card game based on the clichés and oddities of Dungeons and Dragons and other similar role-playing games. Player start at level 1 and the winner is the first player to reach level 10. Players can obtain familiar D&D style character classes during the game which determine to some extent the cards they can play.

There are two kinds of cards - encounteres and treasures. Every turn the current players 'kicks down the door' - taking an encounter card from the deck. Usually this involves fighting a monster. Monsters will have their own levels and players must attempt to overcome it using the levels, weapons and powers they have acquired during the game or run away. Other players can chose to aid the player or hinder by adding extra monsters to the encounter. Defeating a monster will usually result in getting treasure cards and acquiring levels. Being beaten by a monster ends up in "bad stuff" which usually involves losing levels and treasure.