In Zombies Ate My Neighbors, the player takes the role of a male or female protagonist (Zeke or Julia), fighting vampires, mummies, zombies, and other horrifying creatures. The goal is to destroy these monsters, survive the 50+ levels (not including secret ones), and rescue the neighbors that have survived the onslaught.

There is a defined number of neighbors who can be saved on every level. When they are all rescued, an "Exit" door opens, and the player advances to the next level. The levels range from mall and grocery store to beaches and football fields. Using different weapons such as bazooka or water gun, Zeke and Julia have to kill regular enemies and bosses (huge babies, dragons, ants, and others) at the end of the levels. Despite the horror theme, the game's setting contains humorous elements as well. A two-player cooperative mode is available.