Plague Inc. is a strategic simulation game. At the beginning of the game, the player has a pathogen that no one has been infected with yet. The player needs to spread the pathogen throughout the world and destroy everyone in the world by improving the pathogen.

 However, human scientists will develop an antidote, so players will have to complete the goal of eliminating all humans before the antidote is developed or begins to be developed.Players will have to face three problems at the same time: prestige (if the epidemic prevention measures are too aggressive or the epidemic spreads and the mortality rate is too high, the prestige will drop and the game will fail once it reaches 0); rebellion (the people may not cooperate with the quarantine measures and a territory-wide uncooperative movement will break out); and pathogens.

Players can choose from a variety of pathogens in the game, each with its own unique evolutionary approach. However, newcomers just entering the game are generally limited to using bacteria. Subsequent pathogens, including viruses, fungi, parasites, prions, nanoviruses, and bioweapons, generally require the player to play through them in order to unlock them. There are also special pathogens, including the Neurax worm, which can control human minds, the Necroa zombie virus, the "Ape Flu" in collaboration with Rise of the Planet of the Apes Productions, and the vampire plague, named the Shadow Plague. In addition, the game also has special plot modes (for example: mad cow disease, worms that make the world happy).