Munchkin Apocalypse is a core set in the Munchkin series with an end of the world theme that includes natural disasters, Armageddon, zombie takeovers, alien invasions, nuclear war, etc. And while this is still a standard Munchkin game where you attempt to level up by killing the monsters, stealing the treasure, and stabbing your buddy, there's a new "Seal" mechanic that significantly alters the gameplay.

The Seals are a reference to the biblical seals of the Apocalypse. They can be opened and closed, although it is typically more difficult to close them. Once seven Seals are open, the game is over immediately, and the player with the highest combat strength (excluding levels) is the winner. The Seal mechanic adds a sense of impending doom to the game, meant to mimic the sense of impending doom from a real apocalypse. It also tends to create situations where the group works together to close a Seal in order to keep a player from winning via the Seal mechanic. So there is more teamwork than in a typical Munchkin game.

The balance of the deck is also different compared to the other Munchkin sets. There are a many more Disaster cards, which are equivalent to traps and curses, so bad things tend to occur more frequently. Also, there are more monsters, especially the high-level monsters. To balance this, however, there are more item enhancers and high-bonus items. It has been stated in the Munchkin forums that Munchkin Apocalypse is harder to play and is intended more for seasoned Munchkin veterans.

Munchkin Apocalypse has four new classes but does not contain races, powers, or other "thingies". It comes with Undead and Shark monsters, which follow special rules.

The game includes 180 cards (92 Doors, 76 Treasures, 12 Seals). The Seal cards are a different size than the regular cards--they are square and are shorter but wider (2.75" x 2.75"). The included d6 dice is orange with lime green pips, similar in color to the orange dice in the +6 Bag o' Radioactive Munchkin d6.